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PubMed2001

Treatment with paracetamol in infants.

BACKGROUND: Paracetamol (N-acetyl-p-amino-phenol) or acetaminophen has become the most widely used analgesic and antipyretic in children. However, there is a wide discrepancy between the extent to which paracetamol is used and the limited available pharmacological data in small infants. The purpose of this article is to present a review of the current literature regarding the use of paracetamol in neonates and infants with a particular emphasis on pharmacological issues. METHODS: A MEDLINE search (up to March 2000) was conducted to identify relevant English-language publications using paracetamol, children, infants and neonates as search terms. Additional studies were identified from bibliographies of the reviewed literature. RESULTS: Pharmacological studies on paracetamol in infants are few. Most studies have focused on the administration of one single paracetamol dose, and the problem of cumulative toxicity with repeated dosing has not been addressed. Plasma paracetamol concentration should be 10-20 mg ml(-1) to achieve antipyretic and analgesic effects. The bioavailability of the different formulations and routes of administration vary with age. Rectal absorption is slower and more erratic than the oral; however, in the very young, rectal bioavailability is higher than in older patients. Volume of distribution seems to be age-independent, whereas clearance is reduced in neonates and particularly in preterm babies. Neonates and infants are capable of forming the reactive intermediate metabolite that causes hepatocellular damage, particularly after multiple doses. They have an immature glucuronide conjugation system, but the rate constant for the sulphation metabolic pathway is larger than in older children, and this is the most important route of metabolism. CONCLUSIONS: The pharmacokinetics and pharmacodynamics of paracetamol differ substantially in neonates and infants from those in older children and adults; hence, dosing should be adjusted accordingly.

Acetaminophen↗

PubMed1981

Enhanced intestinal absorption of insulin in rats in the presence of sodium 5-methoxysalicylate.

Sodium 5-methoxysalicylate, previously shown to enhance the rectal absorption of several drugs, facilitates the absorption of insulin from the upper gastrointestinal tract, resulting in significantly elevated insulin levels and lowered glucose concentrations in the plasma of rats. Restricting the movement of insulin and adjuvant down the intestine by either ligation or use of a more viscous vehicle further increased the absorption of insulin.

Animals↗

PubMed1984

Characteristics of drug absorption via the rectal route.

The characteristics of drug absorption from the colorectal area are summarized as follows: colorectal absorption is a simple diffusion process through the lipoidal membrane in which carrier-mediated mechanisms play no role; most of the rates of absorption increase with increasing solubility and release of drugs by vehicles or adjuvants, although drug-adjuvant interaction is related to the decreased absorption rate; membrane-active adjuvants promoting absorption are more effective in the colorectal area than in the upper gastrointestinal tract; the promotive effect on absorption by fatty acids or their monoglycerides in micellar state is stronger in unsaturated long-chain compounds than in saturated ones, and their action is transient; their promotive absorption is applicable not only to small molecules but also large molecules, probably up to molecular weights of 500,000; and the threshold molecular weight of the blood-lymph permselectivity of dextrans is approximately 17,500-39,000 in the small intestine and 10,500-17,500 in the large intestine.

Adjuvants, Pharmaceutic↗

PubMed2004

Bioavailabilities of rectal and oral methadone in healthy subjects.

AIMS: Rectal administration of methadone may be an alternative to intravenous and oral dosing in cancer pain, but the bioavailability of the rectal route is not known. The aim of this study was to compare the absolute rectal bioavailability of methadone with its oral bioavailability in healthy humans. METHODS: Seven healthy subjects (six males, one female, aged 20-39 years) received 10 mg d(5)-methadone-HCl rectally (5 ml in 20% glycofurol) together with either d(0)-methadone intravenously (5 mg) or orally (10 mg) on two separate occasions. Blood samples for the LC-MS analyses of methadone and it's metabolite EDDP were drawn for up to 96 h. Noninvasive infrared pupillometry was performed at the same time as blood sampling. RESULTS: The mean absolute rectal bioavailability of methadone was 0.76 (0.7, 0.81), compared to 0.86 (0.75, 0.97) for oral administration (mean (95% CI)). Rectal absorption of methadone was more rapid than after oral dosing with Tmax values of 1.4 (0.9, 1.8) vs. 2.8 (1.6, 4.0) h. The extent of formation of the metabolite EDDP did not differ between routes of administration. Single doses of methadone had a duration of action of at least 10 h and were well tolerated. CONCLUSIONS: Rectal administration of methadone results in rapid absorption, a high bioavailability and long duration of action. No evidence of presystemic elimination was seen. Rectal methadone has characteristics that make it a potential alternative to intravenous and oral administration, particularly in cancer pain and palliative care.

Administration, Oral↗

PubMed1993

Treatment of Strongyloides stercoralis hyperinfection syndrome with thiabendazole administered per rectum.

There is a rising interest in Strongyloides stercoralis infection due to the expanding population of immunosuppressed patients. Currently the drug of choice for both enteric and tissue forms of infection with this organism is oral thiabendazole. We report a patient with a small bowel obstruction due to S. stercoralis hyperinfection who was unable to take thiabendazole orally. Thiabendazole was administered rectally, and the hyperinfection syndrome resolved. Peak serum concentrations of thiabendazole were achieved 4 hours after rectal administration, and drug levels were sustained longer than previously reported with oral dosing. In addition, elevated levels of thiabendazole metabolites in the patient's urine further confirmed significant absorption. Rectal administration of thiabendazole should be considered for patients unable to take the medication orally.

Administration, Rectal↗

PubMed1997

Pharmacokinetics of intrarectal nalbuphine in children undergoing general anaesthesia.

The pharmacokinetics of nalbuphine (0.3 mg/kg) administered by the rectal route were studied in ten children undergoing general anaesthesia for minor surgery. Blood sampling was carried out for 8 h after rectal administration and plasma drug concentrations were measured by high performance liquid chromatography using electrochemical detection after an optimized solid-phase extraction procedure. The mean time to achieve the maximum plasma concentration (Cmax = 24 +/- 15 ng/mL) was 25 +/- 11 min and the elimination half-life was 2.7 +/- 0.7 h. The coefficients of variation for Cmax and the concentration-time curve (AUC) were 62 and 68%, respectively. Although rectal absorption is considered irregular, the large intersubject variability is also explainable by a variable hepatic bypass for a drug, like nalbuphine, that undergoes extensive first-pass metabolism. No problem of analgesic efficacy or of local tolerance was reported. In conclusion, the rectal route of administration provides a rapid and reliable absorption of nalbuphine.

Administration, Rectal↗

PubMed1993

Enhanced absorption of bumetanide from suppositories containing weak acids in rabbits.

The in vitro release of bumetanide from macrogol suppositories with and without weak acids (citric acid and tartaric acid) was studied. The release of bumetanide was not affected when weak acids were added to the suppositories. The in vivo rectal absorption of bumetanide from the suppositories was evaluated in rabbits. The bioavailability (absolute), expressed as the ratio of the area under the plasma concentration-time curve (AUC) following oral administration of bumetanide, was 39% that of intravenous administration. The value in bumetanide following rectal administration of the suppositories without weak acids was 32%. Each absolute bioavailability following rectal administration of the suppositories with 5% citric acid and 5% tartaric acid was 52% and 42%, respectively. These values were significantly larger than those of rectal administration of the suppositories without weak acids. Particularly, the bioavailability following rectal administration of the suppositories containing citric acid was significantly different from even those of oral administration. The absorption rate constants of bumetanide from the suppositories with weak acids were significantly larger than those following oral administration. These results indicated the possibilities of the rectal route of administration of drugs which are weak organic acids and show low or variable bioavailability following oral administration.

Administration, Oral↗

PubMed1984

[Bioavailability of codeine and paracetamol in a combination preparation following oral and rectal administration].

The plasma concentrations of acetaminophen (paracetamol) and codeine were determined in a cross-over study in twelve healthy volunteers after oral and rectal application of a compound preparation. The relative bioavailability from the two forms of application was also computed. The two active substances showed almost parallel plasma concentration paths, and thus were systemically available at the same time. The maximum levels in plasma were already reached after one to two hours. In both active substances the suppositories displayed a classical retardation effect. In contrast to acetaminophen the rectal absorption of codeine was almost as effective as the oral absorption. Thus this application form shows almost bioequivalency vis-à-vis the capsule form. Based on these results the rectal form of administration of codeine as well as the combination of this substance with acetaminophen can be regarded, from the pharmacokinetic point of view, as a rational enhancement of the treatment of various forms of pain.

Acetaminophen↗

PubMed1991

Concealed rectal opiates presenting as respiratory arrest: the importance of rectal examination in i.v. drug abusers.

A case of recurrent respiratory depression due to rectal absorption of concealed opiate drugs in an intravenous drug abuser held in police custody is described. The importance of rectal examination in intravenous drug abusers in police custody is stressed and it is emphasised that drugs may have been concealed in a body cavity at the time of arrest. The use of both the intramuscular and intravenous route for the administration of naloxone in treatment of unconscious intravenous drug abusers suspected of having overdosed on opiates is advocated as these patients frequently discharge themselves from hospital on regaining consciousness and may later present with recurrent respiratory depression.

Adult↗

PubMed1986

Intestinal absorption of sodium cefoxitin in rats: effect of formulation.

The absorption of cefoxitin from rat intestine, rectum and small intestine was greater when the powdered form was administered than when an aqueous solution was given. Cefoxitin absorption from the small intestine was significantly increased after its administration in suppository form prepared with a triglyceride base, although rectal absorption from the suppository did not differ from that of the drug in powdered form. The increase in absorption by the small intestine from the suppository form may be due to fatty acids produced from triglyceride by lipase.

Animals↗

PubMed1984

Promoting effect of concanavalin A on transport of sodium cefoxitin and phenol red from rat rectal compartment.

Concanavalin A enhanced the rat rectal absorption of phenol red and cefoxitin at pH 7.4 and the uptake of cefoxitin into brush border membrane vesicles prepared from rat rectal membrane. The enhancing action of concanavalin A demonstrated a sodium ion dependency and was inhibited by the presence of 4,4'-diisothiocyano-2,2'-disulfonate stilbene and phlorizin. This inhibition suggests the involvement of the membrane protein fraction.

Animals↗

PubMed2004

Evaluation of sustained release suppositories prepared with fatty base including solid fats with high melting points.

To prepare the sustained release suppositories, solid fats such as polyglycerol ester of fatty acids (PGEFs) or beeswax were utilized with a fatty suppository base, Witepsol H15. PGEFs such as decaglycerol heptabehenate (HB750) and hexaglycerol pentastearate (PS500), and beeswax have relatively high melting points. The addition of PGEFs or beeswax to Witepsol H15 increased the apparent viscosity of suppository bases at 37 degrees C without any large change in the melting point of Witepsol H15. Moreover, the apparent viscosity of a mixed base with HB750, PS500 or beeswax at 37 degrees C was significantly correlated with the amount of each solid fat in a mixed base. The release of acetaminophen (AAP), a model drug, from suppositories was delayed by HB750, PS500 or beeswax, and an excellent correlation was observed between the apparent viscosity of these mixed bases and Higuchi's rate constants in each mixed base suppository, suggesting that these solid fats could regulate the drug release from the mixed base suppositories by changing their viscosity. In the in vivo absorption study in rats, several suppositories made from Witepsol H15-HB750 or Witepsol H15-beeswax mixed bases prolonged the rectal absorption of AAP without reducing AUC. In conclusion, by using solid fats such as HB750 and beeswax with relatively high melting points, it is possible to control the rate of drug release from fatty base suppositories for maintaining the plasma concentration of drugs for longer time periods.

Acetaminophen↗

PubMed2001

Relative hypoglycemic effect of insulin suppositories in diabetic beagle dogs: optimization of various concentrations of sodium salicylate and polyoxyethylene-9-lauryl ether.

The effect of insulin suppositories containing different amounts and concentrations of sodium salicylate (50, 100 mg) and polyoxyethylene-9-lauryl ether (POELE 1, 3, 4%), respectively, on the plasma glucose concentration of diabetic beagle dogs was investigated after rectal administration. Comparison of the effects of these formulations was made with that produced after subcutaneous insulin injections. Insulin suppositories containing sodium salicylate (50 mg) produced a maximum reduction of plasma glucose concentration (Cmax) of 55 +/- 11%, an area under the curve (AUC) of 252 +/- 59% reduction h; and a relative hypoglycemia (RH) of 49 +/- 12% relative to subcutaneous injection of insulin (4 U/kg). Increasing sodium salicylate to 100 mg/suppository did not improve the hypoglycemic effect of insulin suppositories further. Investigation of the influence of insulin suppositories containing different concentrations of the nonionic surfactant POELE (1, 3, 4%) showed that; the suppositories containing the lowest concentration (1%) produced the highest hypoglycemic effect with a Cmax of 68%, AUC of 332 +/- 67% reduction h, and RH of 55 +/- 11%. Incorporation of sodium salicylate 50mg in insulin suppositories containing 1% POELE did not improve further the effects found with these suppositories. In conclusion, a relative hypoglycemic effect of about 50-55% can be achieved using insulin suppositories containing Witepsol W35 as a base, insulin (5 U/kg), and sodium salicylate (50 mg) or POELE (1%) as rectal absorption enhancers.

Administration, Rectal↗

PubMed1993

In vitro release of testosterone from suppository bases and in vivo absorption studies in human males.

Diffusion rates of testosterone from various suppository bases with and without surfactants were determined. In a limited study, selected suppository formulations were evaluated for efficiency of rectal absorption of testosterone in three male volunteers ranging in age from 25 to 30 years. Significant reductions in the ratios of urinary metabolites to free testosterone were observed with polyethylene glycol 1000, esterified (C10-C18) fatty acids, and theobroma oil-based samples.

Adult↗

PubMed1984

[Comparative studies on the bioavailability of paracetamol from suppositories].

In a comparative study with 10 healthy male volunteers three paracetamol preparations (two commercial products and one preparation with micronized paracetamol) are tested. No differences in absorption and elimination rate as well as in bioavailability are determined. Reported variations in absorption rate and bioavailability can be explained by different vehicle volumes which were applicated. The vehicle volume, that means the dimension of the rectal absorption area is main factor for interpretation of pharmacokinetic data. The micronization of the drug leads to a sustained release. This result is in correlation with in vitro studies.

Acetaminophen↗

PubMed1998

Absorption enhancement in intestinal epithelial Caco-2 monolayers by sodium caprate: assessment of molecular weight dependence and demonstration of transport routes.

Sodium caprate (C10), a medium chain fatty acid, is used clinically to enhance rectal absorption of the low molecular weight (MW) drug ampicillin. The main aim of this study was to investigate whether C10 also enhances the permeability of high MW model drugs in a model of the intestinal epithelium. The second aim was to present visual evidence of the route of enhanced transport across the epithelial cell layer. The studies were performed in Caco-2 monolayers cultured on permeable supports. The effects of non-toxic concentrations (< or = 13 mM) of C10 on drug transport across the monolayers was studied using monodisperse 14C-polyethylene glycols (MW 238-502; 14C-PEGs), 125I-Arg5-vasopressin (MW 1,208), 125I-insulin (MW 6,000) and FITC-labelled dextrans (MW 4,400 and 19,600; FD4 and FD20 respectively) as model drugs. Electron and confocal laser scanning microscopy were used to demonstrate transport routes across the epithelium. 10 mM C10 increased the permeability of all 14C-PEGs to approximately the same extent. 13 mM C10 increased the permeability of 125I-Arg8-vasopressin 10-fold. Only small increases in FD4 and FD20 permeabilities were observed. After C10 exposure, both tight junctions with normal morphology and those with dilatations showed an increased permeability to ruthenium red, indicating that C10 enhanced the paracellular transport of molecules with a MW < 1,000. Confocal microscopy showed that C10 increased the transport of FD4 and FD20 by the paracellular route. In conclusion, non-toxic concentrations of C10 can be used to enhance the permeability of drugs of MW up to approximately 1,200. Enhancement of the absorption of molecules larger than 4,000 is quantitatively insignificant. The enhanced permeability occurred via the paracellular pathway.

Biological Transport↗

PubMed1976

Absorption and distribution of radioactivity from suppositories containing 3H-benzocaine in rats.

The effects of the suppository vehicle, drug concentration, and nonionic surfactants on in vitro benzocaine dialysis through a cellulose membrane and on rectal absorption in rats of total radioactivity following administration of 3H-benzocaine were investigated. In vitro dialysis correlated quite well with in vivo absorption, and drug release was greater from water-soluble vehicles than from oleaginous vehicles. Inclusion of a nonionic hydrophilic or lipophilic surfactant in cocoa butter resulted in a statistically significant increase for in vitro drug release, while a lipophilic surfactant showed little effect in vivo and a hydrophilic surfactant depressed release in vivo. Both types of surfactant had small effects on release from polyethylene glycol. In vitro release of benzocaine from some commercially available suppositories was compared with experimental preparations. Variation in blood radioactivity following administration of the same concentration of 3H-benzocaine in the same dosage form in male and female rats is reported.

Animals↗

PubMed1990

Absorption enhancement of rectally infused insulin by sodium tauro-24,25-dihydrofusidate (STDHF) in rats.

The bile salt derivative sodium tauro-24,25-dihydrofusidate (STDHF) has been reported to promote nasal absorption of insulin. In the present study the effect of STDHF on rectal insulin absorption was investigated in rats. At concentrations of 1 and 4% (w/v) it enhanced insulin bioavailability from 0.2 +/- 0.2 (control) to 4.2 +/- 3.2 and 6.7 +/- 2.1%, respectively, as assessed by radioimmunoassay. Insulin preparations with STDHF reduced blood glucose concentrations considerably in a concentration-dependent way. Coadministration of STDHF with Na2EDTA (0.25%, w/v) tended to increase further insulin bioavailability and hypoglycemic response. Varying the site of rectal administration did not influence these parameters.

Administration, Rectal↗