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PubMedDate not supplied

Clinical pharmacokinetics of ergotamine in migraine and cluster headache.

Ergotamine has been in use for the treatment of migraine for a century and is still considered to be the most effective therapeutic agent for acute attacks. Only during the last few years have assays been developed, enabling its pharmacokinetics to be studied. Appropriate assays for determining ergotamine concentrations in plasma are radioimmunoassay and high-performance liquid chromatography. There is great interindividual variation in absorption of ergotamine in both patients and normal volunteers. Bioavailability is of the order of 5% or less by oral or rectal administration. After intramuscular or intravenous administration, plasma concentrations decay in a biexponential fashion. The elimination of half-life is 2 to 2.5 hours and clearance is about 0.68 L/h/kg. As yet, formal pharmacokinetics following oral dosing have not been determined. There is some evidence that ergotamine enters the cerebrospinal fluid. Metabolism occurs in the liver, and the primary route of excretion is biliary. Up to 90% of migraine patients experience complete or partial symptom relief after ergotamine, providing the drug is given as early in their attack as possible. Efficacy is greatest after parenteral administration, although adverse effects may make the rectal or inhaled routes preferable. There is some evidence to suggest that good responses are associated with plasma concentrations of 0.2 ng/ml or above within one hour of administration. The mode of action of ergotamine in migraine may be by means of selective arterial vasoconstriction on certain cranial vessel beds or, alternatively, by depression of central serotonergic neurons mediating pain transmission or circulatory regulation. Principal adverse effects of ergotamine include nausea, vomiting, weakness, muscle pains, paraesthesiae and coldness of the extremities. Ergotamine dependence is not uncommon, resulting in an exacerbation of the above symptoms. Dosage must therefore be limited to no more than 10mg per week to minimise toxicity.

Administration, Oral↗
PubMed1998

Buccal absorption of midazolam: pharmacokinetics and EEG pharmacodynamics.

PURPOSE: To determine whether buccal/sublingual administration of midazolam (MDL) would lead to detectable venous concentrations and EEG changes in 10 healthy volunteers. METHODS: The study consisted of an open-label and a double-blind phases. Subjects held 10 mg MDL in 2 ml peppermint-flavored fluid or peppermint-flavored placebo in their mouth for 5 min and then spat it out. Cardiorespiratory and EEG monitoring was performed in all subjects. RESULTS: Venous MDL concentrations measured on 10 occasions from 5 to 600 min after administration showed a rapid increase for the first 20-30 min. However, changes in the 8- to 30-Hz frequencies identified by spectral analysis of the EEG showed changes in < or = 5-10 min in test but not in control subjects--more rapid than were expected from the venous absorption data. There were no significant adverse effects. CONCLUSIONS: Our data provide direct evidence of the speed of cerebral effect of a drug. Our results suggest that the buccal/sublingual route of administration should be tested in emergency treatment of seizures as an alternative to the rectal route, over which it has clear practical advantages.

Absorption↗
PubMed1991

Clinical and physiological study of anal sphincter and ileal J pouch before preileostomy closure and 6 and 12 months after closure of loop ileostomy.

Spontaneous evolution of pouch and anal function, and absorption features has been assessed in 15 patients who underwent proctocolectomy with J ileal pouch anastomosis without conservation of a rectal muscular cuff. All the patients were studied before preileostomy closure and six and 12 months after the closure of the protection loop ileostomy. Stool frequency was identical at six and 12 months (mean +/- SEM: 5.0 +/- 0.4 and 5.3 +/- 0.5/day, respectively). Sixty-six percent of patients at six months and 40% of patients at 12 months need to defecate at least one time during night. Stool weight as well as steatorrhea decreased significantly six months after the closure of loop ileostomy (P less than 0.05). Mean resting anal pressure remained unchanged six and 12 months after closure of the loop ileostomy (41 +/- 6 and 45 +/- 5 cm H2O, respectively). Maximum squeeze anal pressures increased significantly at six (P less than 0.05) and 12 months (P less than 0.05). The rectoanal inhibitory reflex was always absent at the same period. The maximum pouch capacity increased significantly during the first six months (P less than 0.01) from 142 +/- 17 to 279 +/- 27 ml. The maximum infused volume during a saline continence test was not significantly different at six and 12 months; the percentage of evacuation of the reservoir and the volume at which the first ileal contraction appeared in the reservoir increased significantly (P less than 0.05) at six and 12 months. In conclusion, in patients with ileoanal anastomosis and pouch reservoir, the closure of the loop ileostomy is associated with spontaneous modifications of the anal and pouch parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Case report: renal excretion of gastrografin following rectal administration.

Renal excretion of water soluble iodinated contrast media following oral administration has often been described but no reports describing renal excretion following rectal administration of such contrast have previously been described. We describe a case of renal excretion of diatrizoate methylglucamine (Gastrografin, Schering) following a diagnostic 'gastrografin enema' in a woman with caecal carcinoma.

Administration, Rectal↗
PubMed2003

[New perspectives on paracetamol].

Paracetamol (acetaminophen) is well established as a leading non-prescription antipyretic analgesic drug. Future developments are likely to include new formulations to achieve rapid absorption for a fast onset of action, and prolonged absorption to extend the duration of action for regular long-term administration. Better dosage forms are also required for rectal administration. The availability of intravenous paracetamol has greatly extended the use of this drug as an adjunct to postoperative analgesia and for control of fever in the intensive care setting. Intravenous paracetamol is available in only a few countries at present, but it seems inevitable that it will be marketed much more widely in the future. The misuse of paracetamol as a fashionable agent for self-poisoning seems likely to continue, and liver failure may still occur in the small proportion of overdose patients who present too late for effective antidotal treatment with N-acetylcysteine. Much effort is being devoted to the study of the molecular mechanisms of paracetamol hepatotoxicity, and it is hoped that further advances may make it possible to prevent liver failure in all patients, irrespective of delays in presentation. At the same time, there is great interest in the mechanisms of the therapeutic actions of paracetamol and its effects on the different isoforms of cyclo-oxygenase. There will probably be important new findings in this area and these may lead to wider clinical use. Meantime, possible novel therapeutic applications for paracetamol include its use as an antioxidant to prevent atherosclerosis and cardiovascular disease by inhibiting the oxidation of low-density lipoproteins, and to prevent the formation of cataracts.

Acetaminophen↗
PubMed1997

Morphometry of the small intestine in pigs with ileo-rectal anastomosis.

Ileo-rectal anastomosis (IRA), which is frequently used to measure prececal digestibility in pigs, could induce some disturbances of the normal absorptive function. Our aim was to investigate the effects of different IRA surgical procedures on the main histologic characteristics of the small intestine in pigs. The 4 different IRA procedures compared to intact pigs (INT) were the following: either end to end (EE) or end to side (ES) with or without preservation of the ileocecal valve (EEV, EE, ESV, ES respectively). At 147 d after surgery, samples of the wall of the duodenum, jejunum and ileum were taken under anesthesia and histometric examinations were performed on HE- and PAS-colored sections to estimate changes mainly of mucosa and muscle layers. The values recorded for villus length, crypt depth, and whole thickness of the mucosa suggested that the EE procedures disturb the small intestine less than the ES models. A new parameter, called epithelial quotient and calculated as [(villus length/crypt depth)/mitotic index], was proposed to improve the comparisons. According to this quotient, EE procedures did not significantly affect the mucosa of the whole small intestine. An increased density of goblet cells was recorded in all operated pigs along the small intestine, but mainly in the ileum after EE-IRA. The lymphatic follicle area was reduced. These findings, which were in agreement with a reduced mitotic index in the ileum of EE-pigs, indicated a decreased effect of noxious factors on the small intestinal mucosa in IRA-pigs, especially after the EE-IRA procedure. Some atrophic or hypertrophic effects on the muscle layers were related to the absence or preservation of the ileo-cecal valve. Finally it was concluded that i) there was no major disturbance after IRA, and ii) the end to end procedure was most beneficial for the structural integrity of the small intestine.

Anastomosis, Surgical↗
PubMed1991

Absorption of paracetamol from suppositories in geriatric patients with fecal accumulation in the rectum.

The bioavailability of paracetamol from suppositories was studied in 16 geriatric in-patients in stable clinical condition; 9 had significant amounts of feces in the rectum. Rectal accumulation of feces reduced the peak plasma paracetamol concentration by 32% (p = 0.05) and the AUC0-8h by 27% (p = 0.04). The peak concentration, however, appeared earlier among patients with rectal accumulation of feces. Compared to findings in 6 healthy young controls, geriatric patients had higher plasma concentrations of the main paracetamol metabolites.

Acetaminophen↗
PubMed1982

Temperature and adrenocortical responses in rhesus monkeys exposed to microwaves.

To determine if the endocrine response to microwave exposure was similar in a primate to that reported for other animals, rectal temperature and plasma levels of cortisol, thyroxine (T4), and growth hormone (GH) were measured in rhesus monkeys exposed to 1.29 GHz microwave radiation. Exposures were carried out under far-field conditions with the monkey restrained in a chair. Incident power densities of 0, 20, 28, and 38 mW/cm2 were used, with corresponding specific absorption rates of 0, 2.1, 3.0, and 4.1 W/kg. Blood samples were taken hourly via an indwelling jugular venous catheter over a 24-h period before, during, and after an 8-h exposure. Rectal temperature increased an average of 0.5, 0.7, and 1.7 degrees C for the three intensities used. No changes in T1 or GH were observed. Cortisol levels were increased during exposure to 38 mW/cm2. It was concluded that the temperature and adrenocortical responses to microwave exposure of the rhesus monkey are similar to the corresponding responses of other animals.

Adrenal Cortex↗
PubMed1990

The pharmacokinetics of artemisinin after oral, intramuscular and rectal administration to volunteers.

The pharmacokinetics after oral, intramuscular and rectal administration of artemisinin, a new potent antimalarial drug, to healthy volunteers has been examined. The study was set-up as a four-way cross-over design with a wash-out period of one week between the test days. In ten volunteers artemisinin concentrations in serum were monitored using a reversed phase HPLC assay with UV detection after derivatization. After oral administration, artemisinin was rapidly but incompletely absorbed, the mean absorption time was 0.78 h and the bioavailability relative to the intramuscularly injected suspension in oil 32%. The mean residence time of the latter (10.6 h) was 3 times that of the oral formulation (3.4 h). This seems to enable a twice daily dosage regimen for the intramuscular oil injection, while the oral formulation necessitates a more frequent dosing interval. After intramuscular injection and rectal administration of an aqueous suspension, very low and variable artemisinin concentrations in serum were observed, probably indicating a poor and erratic absorption.

Administration, Oral↗
PubMed1991

[Gastrointestinal absorption of theophylline, especially with reference to retard preparations].

Little is known about the absorption of theophylline from definite parts of the intestine, though there are many depot or slow-release formulations of theophylline on the market and this topic should be of relevant importance. Most of these formulations are releasing the drug for up to 24 hours while passing the bowels. In this prospective, open, randomised, study with an interchange trial design the absorption of theophylline from the colon was studied in eight healthy male volunteers: 400 mg theophylline was given intravenously and in two different forms into the colon transversum by application with an endoscope. Under these conditions, theophylline was absorbed in an amount of 54% on the average with some variation due to the applied formulation. Therefore, it could be concluded that theophylline is absorbed to a clinically relevant extent from the large intestine. These results are remarkable with regard to the development and pharmaceutical profiles of retard or slow-release formulations of theophylline and the undesired effects of this therapy.

Administration, Rectal↗
PubMed1996

Pharmacokinetics and drug input characteristics for a diclofenac-codeine phosphate combination following oral and rectal administration.

In a single dose cross-over study with 12 healthy male volunteers the plasma concentrations of diclofenac (CAS 15307-86-5) and codeine (CAS 76-57-3) were determined after oral and rectal application of formulations containing 50 mg of each drug. For kinetic analysis of the concentration-time profiles non-compartmental as well as compartmental procedures were used. The compartment model included two disposition compartments supplemented by a dissolution and drug absorption step. For both compounds, the AUC0-infinity values of the two treatments were similar with only a slightly higher AUC for the suppositories, which was not found to be significantly different under the employed conditions (p > 0.05). Referring to the pharmacokinetic parameters Cmax and tmax typical differences between oral and rectal formulations were observed. For the suppositories, diclofenac and codeine average peak plasma concentrations were only half as high as for the tablets, whereas the respective tmax values were doubled. The results obtained show a similar extent of diclofenac and codeine bioavailability for both administration routes, but the rate of drug input was lower for the suppositories. The total mean input time (MITtot) was found to be significantly longer for the suppositories. This seems to be caused by a slow release from the dosage form or dissolution of the drugs, which is confirmed by a longer MITtot compared to the MRTsys in most of the volunteers.

Administration, Oral↗
PubMed2003

Evaluation of efficiency of insulin suppository formulations containing sodium salicylate or sodium cholate in insulin dependent diabetic patients.

Two formulations of insulin suppositories were prepared to contain different amounts of sodium salicylate and sodium cholate as absorption promoters and also of insulin with the purpose of obtaining the most effective formulation in reducing plasma glucose levels after rectal administration to diabetic patients. The results show that insulin suppositories containing 100 mg sodium salicylate and 100 or 200 U of crystalline insulin showed no significant difference in AUC, Cmax and Tmax and both formulations showed significant reduction in plasma glucose level compared to initial values within 1.5-2 h. The results from experiments carried out in health volunteers showed that 100 mg sodium salicylate is the optimum amount to be included in insulin suppositories producing significantly higher Cmax and AUC compared to those produced after rectal administration of insulin suppositories containing 50 or 200 mg sodium salicylate. The results also show that using sodium cholate in 50 mg amount did not produce any significant reduction in plasma glucose levels of insulin dependent diabetic patients given suppositories containing 100 U of insulin, but this amount in suppositories containing 200 U of insulin was able to produce significant (p < 0.05) reduction in plasma glucose level within 1 h which lasted till end of experiment producing Cmax of 29.7 +/- 6.61% at Tmax of 1.5 +/- 0.61 h. On increasing the amount of sodium cholate to 100 mg in the suppositories, a marked (p < 0.01) reduction in plasma glucose level took place and the Cmax increased to 47.7 +/- 12.24% at Tmax of 1.5 +/- 0.63 h. This resulted in AUC of 86.7 +/- 22.4 mg%h which was non significantly higher from that produced after administration of suppositories containing 50 mg sodium cholate and 200 U insulin (62.5 +/- 17.6 mg%h). The results also show that insulin suppositories containing 100 mg sodium cholate and 200 U insulin resulted in a non significant differences in Cmax and AUC from those produced by S.C. injection of insulin (20 U) but significantly (p < 0.001) shorter Tmax. This formulation also shows non significant differences in Tmax and AUC and significantly (p < 0.05) higher Cmax than from those produced after rectal administration of suppositories containing 100 mg of sodium salicylate and same amount of insulin. Further more this formulation produced severe hypoglycemia in control healthy volunteers within 1 h of administration producing Cmax of 57.0 +/- 18.8% at Tmax of 0.75 +/- 0.35 h. The results of this study showed that the formulation containing 100 mg of sodium cholate and 200 U of insulin tested in fasted insulin dependent diabetic patients produced a maximum % reduction in plasma glucose levels (Cmax) of 47.7 +/- 12.24% at tmax of 1.5 +/- 0.63 h compared to Cmax of 50.56 +/- 6.8% at tmax of 2.93 +/- 0.19 h resulted after subcutaneous injection of 20 U insulin. These suppositories produced an area under the curve (AUC) of 87 +/- 22.4 mg%h compared to an AUC of 81 +/- 13.4 mg%h obtained after subcutaneous injection. This formulation of suppositories studied in 7 insulin dependent diabetic patients was found to abolish the 2-h post-prandial significant rise in plasma glucose levels after meal. These results show that these insulin suppositories containing 100 mg of sodium cholate and 200 U of insulin can serve as effective buffer against meal related hyperglycemia. The suppositories were safe, effective, accepted and well tolerated by the tested individuals.

Adult↗
PubMed1981

[Rifampicin (benemycin) treatment of salmonellosis in nursing infants].

The efficacy of rifampicin (benemycin) in combined therapy of salmonellosis in 145 infants, including 25 newborns was studied. The data indicated that it was highly effective and superior to the other drugs, such as levomycetin, polymyxin, ampicillin and furazolidone, widely used at present for the treatment of salmonellosis in children. The efficacy of rifampicin was due to the high sensitivity to it of various Salmonella strains, including polyresistant strains of S. typhimurium, as well as the peculiar characteristics of its pharmacokinetics, i. e. the ability for rapid absorption into the blood, the effect on the bacteria located in the cells and excretion with bile. When used orally or rectally in a daily dose of 15--20 mg per 1 kg bw for a short-term treatment course rifampicin induced no side effects or allergic reactions. It is concluded that rifampicin (benemycin) may be used as a valuable reserve drug for the treatment of the severe forms of salmonellosis caused by polyresistant strains of S. typhimurium in infants and newborns. It is not advisable to use the drug for the treatment of children with moderate and nonsevere forms of salmonellosis since it may be the cause of the development of resistance to it in Salmonella.

Drug Evaluation↗
PubMed1991

Pharmacokinetic study of etodolac after rectal administration; "in vitro" release kinetics.

The present study describes the pharmacokinetic behaviour of a new dosage form of etodolac not available in the Spanish market: suppositories. Rectal administration was chosen as an alternative for the oral route. The dose used was 200 mg. The pharmacokinetic parameters of the drug are estimated by means of two possible methods i.e., model-independent and model-dependent. The results obtained are compared and discussed. At the same time, an "in vitro" study of the release kinetics of etodolac from the suppository was performed using a continuous flow system without fluid recirculation or accumulating reservoir. The dissolution media used were buffered aqueous solutions at pH 6.5 and 7.4. The results obtained show that the release of the drug from the supposity could be a limiting factor for its absorption.

Administration, Rectal↗