Emodin-induced hepatotoxicity was exacerbated by probenecid through inhibiting UGTs and MRP2.

Aggravating effect of probenecid (a traditional anti-gout agent) on emodin-induced hepatotoxicity was evaluated in this study. 33.3% rats died in combination group, while no death was observed in rats treated with emodin alone or probenecid alone, indicating that emodin-induced (150 mg/kg) hepatotoxicity was exacerbated by probenecid (100 mg/kg). In toxicokinetics-toxicodynamics (TK-TD) study, aspartate aminotransferase (AST) and systemic exposure (area under the serum concentration-time curve, AUC) of emodin and its glucuronide were significantly increased in rats after co-administrated with emodin and probenecid for 28 consecutive days. Results showed that the increased AUC (increased by 85.9%) of emodin was mainly caused by the decreased enzyme activity of UDP-glucuronosyltransferases (UGTs, decreased by 11.8%-58.1%). In addition, AUC of emodin glucuronide was increased 5-fold, which was attributed to the decrease of multidrug-resistant-protein 2 (MRP2) protein levels (decreased by 54.4%). Similarly, in vitro experiments proved that probenecid reduced the cell viability of emodin-treated HepG2 cells through inhibiting UGT1A9, UGT2B7 and MRP2. Our findings demonstrated that emodin-induced hepatoxicity was exacerbated by probenecid through inhibition of UGTs and MRP2 in vivo and in vitro, indicating that gout patients should avoid taking emodin-containing preparations in combination with probenecid for a long time.

Preparation of Clinically Useful Sennoside-reduced Rhubarb.

OBJECTIVE: The aim of this study was to develop a method of removing sennoside to reduce the cathartic effect of rhubarb while conserving its other pharmacological activities. METHODS: Rhubarb powder was steam autoclaved at 121°C and 0.14 MPa for 20, 60, or 120 minutes, and HPLC analysis was conducted to determine levels of rhubarb components. Mice were fed non-autoclaved or 20-minute-autoclaved rhubarb extracts. Feces were collected and weighed over a 24-hour period. India ink was orally administered to determine the distance of fecal migration through the intestinal tract. RESULTS: Autoclaving 20, 60, and 120 minutes decreased sennoside A and B to trace levels but only autoclaving 20 minutes conserved most of the (+)-catechin, (-)-epicatechin, and (-)-epicatechin gallate contents (i.e., 69%, 90%, 88%, respectively). Therefore only rhubarb autoclaved for 20 minutes was used in subsequent experiments. Fecal output (in g) in mice treated with water (control), autoclaved rhubarb, and non-autoclaved rhubarb was 2.78 ± 0.07, 3.30 ± 0.13 (p = 0.348), and 3.81 ± 0.07 (p = 0.005). India ink migration was far less in mice treated with autoclaved rhubarb vs non-autoclaved rhubarb. CONCLUSION: Steam autoclaving the rhubarb for 20 minutes reduces sennoside levels and its cathartic activity while conserving its other pharmacological activities.

Kidney injury after sodium phosphate solution beyond the acute renal failure.

BACKGROUND AND OBJECTIVES: Screening colonoscopy with polipectomy reduces colonorectal cancer incidence and mortality. An adequate bowel cleansing is one of the keys to achieving best results with this technique. Oral sodium phosphate solution (OSP) had a widespread use in the 90s decade. Its efficacy was similar to polyethylene glycol (PEG) solution, but with less cost and convenient administration. Series of patients with acute renal failure due to OSP use have been reported. However, large cohorts of patients found no difference in the incidence of renal damage between these two solutions. METHODS: From 2006 to 2009 we identified twelve cases of phosphate nephropathy after colonoscopy prepared with OSP. All patients were followed up to six months. All patients had received just a single dose. RESULTS: We analyzed 12 cases with phosphate nephropathy; three patients debuted with AKI and nine patients had chronic renal injury. Four cases were confirmed with renal biopsy. One patient with AKI needed hemodialysis at diagnosis without subsequent recovery. Two patients (both with chronic damage) fully recovered their previous renal function. The remaining patients (nine) had an average loss of estimated glomerular filtration rate of 24ml/min/1.73m(2). CONCLUSIONS: The use of OSP can lead to both acute and chronic renal damage. However, chronic injury was the most common pattern. Both forms of presentation imply a significant and irreversible loss of renal function. Further studies analyzing renal damage secondary to bowel cleaning should consider these two different patterns of injury.

Investigations of bisacodyl with modified ß-cyclodextrins: Characterization, molecular modeling, and effect of PEG.

Bisacodyl inclusion into hydroxypropyl-ß-cyclodextrin and 2,6-di-O-methyl-ß-cyclodextrin cavities was experimentally and theoretically investigated, and the effect of PEG 4000 on these inclusions was studied. Isothermal calorimetry titration curves indicated that the binary inclusion processes are enthalpy- and entropy-driven. The solid-state complexes were fully characterized by FT-IR, XRPD, DSC and SEM analyses. FT-IR, (1)H NMR, and ROESY studies provided the most favorable encapsulation modes of binary complexes, and results were further confirmed by molecular docking and molecular dynamics studies. The presence of PEG 4000 slightly enhanced encapsulation efficiency, solubility and dissolution rates of the binary complexes. In vivo studies showed that complexes with CDs markedly accelerated gastrointestinal transit time compared with pure bisacodyl, whereas addition of PEG 4000 showed no further significant improvement of the bioavailability.

The pharmacokinetic study on the mechanism of toxicity attenuation of rhubarb total free anthraquinone oral colon-specific drug delivery system.

Rhubarb is commonly used as laxatives in Asian countries, of which anthraquinones are the major active ingredients, but there are an increased number of concerns regarding the nephrotoxicity of anthraquinones. In this study, we compared the pharmacokinetic characteristics of rhubarb anthraquinones in rats after orally administered with rhubarb and rhubarb total free anthraquinone oral colon-specific drug delivery granules (RTFA-OCDD-GN), and then explained why these granules could reduce the nephrotoxicity of anthraquinones when they produced purgative efficacy. A sensitive and reliable high performance liquid chromatography (HPLC) method has been fully validated for simultaneous determination of the five active components of rhubarb, and successfully applied to investigate and compare the remarkable differences in pharmacokinetic study of rhubarb anthraquinones after orally administered with rhubarb and RTFA-OCDD-GN. The results showed that, compared with rhubarb group, the AUC, Cmax, t1/2z and Vz/F of aloe-emodin, rhein, emodin and chrysophanol in rats receiving the RTFA-OCDD-GN were significantly decreased, and the Tmax of the four analytes was prolonged. Moreover, the Tmax of rhein, the Cmax of chrysophanol and emodin all have significant differences (P<0.05). Simultaneously, anthraquinone prototype excretion rates in urine and feces of aloe-emodin, rhein, emodin, chrysophanol and physcion were all increased. These findings suggested that oral colon-specific drug delivery technology made anthraquinone aglycone to colon-specific release after oral administration. This allowed anthraquinones to not only play the corresponding purgative effect but also avoid intestinal absorption and promote excretion. And thereby greatly reduced the nephrotoxicity of rhubarb. The result is a new breakthrough in rhubarb toxicity attenuated research.

Performance of two neutral oral contrast agents in CT enterography.

INTRODUCTION: This study compares the performance of two neutral oral contrast agents in CT enterography (CTE). Mannitol 2.5%, an oral osmotic agent, is compared with psyllium fibre (Metamucil). Both these agents are commonly used, but to our knowledge, they have not been compared in CTE. METHODS: CTE data were collected from 25 consecutive studies for both mannitol and psyllium fibre between 2011 and 2013. All images were reviewed by two radiologists and one registrar blinded to the oral contrast used. Each quadrant was assessed for maximum distension, proportion of bowel loops distended, presence of inhomogeneous content and bowel wall visibility. Overall subjective quality and whether the contrast agent reached the caecum were also assessed. Patients were invited to answer a questionnaire regarding tolerability of the preparations. RESULTS: Wall visibility was rated good in 100% of the mannitol studies, compared with 71% of the psyllium fibre studies, in the right lower quadrant (P = 0.01). No statistically significant difference between groups was observed in either maximal distension or proportion of loops distended in any quadrant. Inhomogeneous material was observed in 12% of the mannitol cases and 86% of the psyllium fibre cases (P < 0.0001). In all mannitol cases, the contrast reached the caecum, compared with 50% of psyllium fibre cases (P < 0.0001), and 36% of the mannitol studies were considered excellent, compared with 20% of the psyllium fibre studies (P = 0.03). CONCLUSION: Mannitol achieves studies of better quality and is now the preferred oral contrast for CTE studies at Auckland City Hospital.

Comparative pharmacokinetics of aloe-emodin, rhein and emodin determined by liquid chromatography-mass spectrometry after oral administration of a rhubarb peony decoction and rhubarb extract to rats.

This study aimed to clarify the rationality of herbaceous compatibility of a rhubarb peony decoction (DaHuang-Mu-Dan-Tang, RPD) by comparing the pharmacokinetics of aloe-emodin, rhein and emodin in rats' plasma after oral administration of RPD and rhubarb extract. A rapid, sensitive LC-MS method was developed and validated for the determination of the plasma concentrations of the three analytes after oral administration RPD and rhubarb extract. The developed method was successfully applied to a pharmacokinetic study of aloe-emodin, rhein and emodin in rats' plasma after oral administration. Compared with administration of single rhubarb, the C(max) of rhein in RPD was decreased significantly (p < 0.05). Meanwhile, the T1/2 of aloe-emodin and emodin were increased significantly (p < 0.05) after administration of RPD. In addition, the T(max) of rhein and emodin were also increased significantly (p < 0.05) in RPD. These results indicated that the absorption of rhein in rats was suppressed after oral administration RPD. Moreover, The time for rhein and emodin to reach the peak concentration was delayed and the elimination of aloe-emodin and emodin was also postponed in RPD. This study could provide a meaningful basis for evaluating the clinical application of traditional Chinese medicine in terms of pharmacokinetics.

Serum electrolyte shifts following administration of sodium phosphates enema.

The misuse of sodium phosphates enemas has resulted in reports of potentially severe metabolic and hemodynamic disturbances. Despite their long availability, these products have not been fully characterized pharmacokinetically. This trial sought to evaluate changes in the metabolic and hemodynamic parameters following the administration of one of two standard sodium phosphates enemas. Enema Casen (250 ml) is available only in Spain, and Fleet Enema (133 ml) is available in 66 countries in six continents of the world. These changes were correlated with scientific literature reports of hyperphosphatemia following phosphate enema use. Forty-five adult participants aged 50 years or older enrolled in the trial. Twenty-five participants were given one Enema Casen, whereas 20 participants received one Fleet Enema. Blood pressure, pulse, and serum chemistries were evaluated at screening; baseline; and 10, 60, and 120 minutes after receiving the enema. Each participant had a bowel movement within 10 minutes of receiving his enema. Asymptomatic, transient hyperphosphatemia was associated with increase in retention time but not with increase in volume of sodium phosphates enemas. Increased serum phosphate concentration and increased area under the curve of serum phosphate were associated with increased enema retention time. The Enema Casen induced a greater mean AUC of serum sodium concentration than did the Fleet Enema. There were no drug-related adverse events. Transient hyperphosphatemia following the use of sodium phosphates enemas correlates with retention time but not with dose. A scientific literature review of serious adverse events revealed that overdose, concomitant use of oral and rectal sodium phosphates products, and use in a contraindicated patient were associated with sodium phosphates enema and hyperphosphatemia.

Bowel preparation: comparing metabolic and electrolyte changes when using sodium phosphate/polyethylene glycol.

BACKGROUND: Many patients with various types of colonic pathology undergo invasive procedures that require mechanical bowel preparation. The most commonly used medications for bowel preparation include phosphate-containing drugs which are low cost and enable this procedure to be performed in an outpatient setting, as opposed to other medications, such as polyethylene glycol. Recent studies have suggested that freely using phosphate-containing drugs might lead to renal function impairment in a small group of patients. Despite this, many surgeons still use these drugs to prepare their patients. We conducted a comparative study to check the side effects of phosphate-containing drugs compared to polyethylene glycol when used for bowel cleansing. METHODS: We conducted a double blind prospective randomized study that included 40 patients undergoing surgery for colonic pathology, all of whom underwent bowel cleansing (20 with sodium phosphate and 20 with polyethylene glycol). During the perioperative course, electrolyte parameters were collected from serum and urine and compared between the two groups of patients. RESULTS: Changes in electrolyte and metabolic parameters were shown in both groups, but more prominently in patients prepared with sodium phosphate. In addition, early signs of renal function impairment appeared in this group. The differences in metabolic and electrolyte changes between the two groups were statistically significant. CONCLUSIONS: On the basis of this study, we propose that the wide use of phosphate-containing drugs for colonic preparation might be dangerous for the specific group of patients that is prone to develop renal failure or electrolyte abnormalities.

Species and gender differences affect the metabolism of emodin via glucuronidation.

The aim of the present study was to define the mechanisms responsible for poor bioavailability of emodin by determining its metabolism using in vitro and in situ disposition models of the intestine and liver. Liver microsomes of mice, rats, guinea pigs, dogs, and humans were used along with the rat intestinal perfusion model and the rat intestinal microsomes. In the rat intestine, excretion rates of emodin-3-O-glucuronide were significantly different (p < 0.05) in four regions of the intestine and were higher in males than in females (p < 0.01). Emodin glucuronidation in liver microsomes was species-dependent, and K (m) values varied 5.7-fold (3.2-18.2 microM) in males and 2.8-fold (4.6-13.0 microM) in females. The male intrinsic clearance (CL(int)) values differed by 5-fold (27.6-138.3 mL h(-1) mg(-1) protein), and female CL(int) values differed by 4.3-fold (24.3-103.5 mL h(-1) mg(-1) protein). Since CL(int) values of emodin glucuronidation were 10-fold higher than that of isoflavones, emodin was considered rapidly glucuronidated. In contrast to the large species-dependent effects on K (m) and CL(int) values, gender had a smaller effect on these kinetic parameters (2-fold, p < 0.05). Lastly, glucuronidation rates obtained using liver microsomes from various experimental animals of the same gender correlated well with those in human liver microsomes. In conclusion, Rapid metabolism by UDP-glucuronosyltransferase is the major reason why emodin has poor bioavailability. Species and gender affected emodin metabolism to a different degree, and experimental animals are expected to be useful in predicting emodin glucuronidation in humans.

A pharmacokinetics evaluation of a new, low-volume, oral sulfate colon cleansing preparation in patients with renal or hepatic impairment and healthy volunteers.

The pharmacokinetics (PK) of an oral sulfate solution (OSS) for bowel cleansing preparation was studied. OSS (30 g of sulfate) was split between 2 doses, 12 hours apart. Safety measures included electrocardiography, vital signs, adverse events, hematology, blood chemistry, and urinalysis. Six adult patients with moderate renal disease (MRD), 6 with mild-moderate hepatic disease (M/MHD), and 6 normal healthy volunteers (NHVs) completed the study. Adverse events were mild to moderate in severity and were mainly limited to headache and expected gastrointestinal symptoms. Serum sulfate levels were highly variable at all times, even after adjusting for baseline. Sulfate was higher in MRD in comparison to the other groups. The C(max) and AUC were higher in the patients, but no statistically significant differences emerged. Sulfate levels returned to predose values within 54 hours after dosing. No electrolyte disturbances occurred. Urinary sulfate excretion was approximately 20% of the dose. OSS was well tolerated. The types and severity of adverse events were similar to those seen in large phase III trials. While patients with MRD had elevated sulfate, the levels were less than those in renal failure and did not alter biochemical parameters that are associated with hypersulfatemia.

Forensic application of ESEM and XRF-EDS techniques to a fatal case of sodium phosphate enema intoxication.

Sodium phosphate enemas and laxatives are widely used for the treatment of constipation, even if a number of cases of significant toxicity due to alterations of the fluid and electrolyte equilibria (hypernatremia, hyperphosphatemia, and hypocalcemia) have been reported. We present the case of an 83-year-old man who died of fecal and chemical peritonitis secondary to an iatrogenic colon perforation (produced performing a Fleet enema through the patient's iliac colostomy) with peritoneal absorption of sodium phosphate. Environmental scanning electron microscopy coupled with an X-ray fluorescence energy dispersive spectrometry discovered multiple bright crystals formed of calcium, phosphorus, and oxygen in the brain, heart, lung, and kidney sections of the victim. The absence of these kinds of precipitates in two control samples chronically treated with Fleet enemas led us to assume that the deceased had adsorbed a great quantity of phosphorus ions from the peritoneal cavity with subsequent systemic dissemination and precipitation of calcium phosphate bindings.

Increased serum phosphate levels and calcium fluxes are seen in smaller individuals after a single dose of sodium phosphate colon cleansing solution: a pharmacokinetic analysis.

BACKGROUND: Sodium phosphate containing colonoscopy preparations may cause electrolyte disturbances and calcium-phosphate nephropathy. Decreased body weight is an unexplored risk factor for complications with sodium phosphate ingestion. AIM: To perform a pharmacokinetic analysis of a single dose of Fleet Phospho-Soda in smaller and larger individuals. METHODS: Seven subjects weighing <55 kg (Group I) and six weighing >100 kg (Group II) consumed 45 mL Fleet Phospho-Soda. Serum electrolytes were measured. Hydration was closely maintained by monitoring weight, fluid intake and total body water. RESULTS: Marked increases in serum phosphate were seen in Group I compared to Group II. For example, mean serum phosphate at 120 min was 7.8 +/- 0.5 mg/dL in Group I and 5.1 +/- 0.8 mg/dL in Group II (P < 0.001). Normalized area under the phosphate vs. time curve for Group I was 1120 +/- 190 mg/dL*min and 685 +/- 136 mg/dL*min for Group II (P < 0.001). Twelve-hour urine calcium was lower in Group I (16.4 +/- 7.6 mg) than in Group II (39.2 +/- 7.8 mg, P < 0.001). CONCLUSIONS: Increased serum phosphate occurs in smaller individuals after ingestion of sodium phosphate preparations, even with strict attention to fluid intake. Smaller body weight poses a potential risk for calcium-phosphate nephropathy.

Sodium picosulfate/magnesium citrate: a review of its use as a colorectal cleanser.

Oral sodium picosulfate/magnesium citrate (CitraFleet; Picolax), consisting of sodium picosulfate (a stimulant laxative) and magnesium citrate (an osmotic laxative), is approved for use in adults (CitraFleet; Picolax) and/or adolescents and children (Picolax) as a colorectal cleansing agent prior to any diagnostic procedure (e.g. colonoscopy or x-ray examination) requiring a clean bowel and/or surgery. It is dispensed in powder form (sodium picosulfate 0.01 g, magnesium oxide 3.5 g, citric acid 12.0 g per sachet), with the magnesium oxide and citric acid components forming magnesium citrate when the powder is dissolved in water. In adult patients, two sachets of sodium picosulfate/magnesium citrate was at least as effective and well tolerated as oral magnesium citrate 17.7 or 35.4 g, or oral polyethylene glycol 236 g in adult patients undergoing a double-contrast barium enema procedure in three large, randomized, comparative clinical studies. In contrast, sodium picosulfate/magnesium citrate was less effective than a sodium phosphate enema preparation in two studies in patients undergoing flexible sigmoidoscopy. A similar number of patients receiving two sachets of sodium picosulfate/magnesium citrate or two 45 mL doses of oral sodium phosphate the day before a double-contrast barium enema procedure achieved satisfactory barium coating and none/minimal faecal residue in one study. However, the data from three of these studies should be interpreted with caution because the administrative regimens used differed from that recommended. Sodium picosulfate/magnesium citrate is also an effective and generally well tolerated colorectal cleansing agent in children and adolescents; the preparation was more effective than oral bisacodyl 0.01 or 0.02 g plus a sodium phosphate enema preparation in this population. Further research is thus required to accurately position sodium picosulfate/magnesium citrate and fully establish its efficacy and tolerability prior to various exploratory or surgical procedures. Nevertheless, oral sodium picosulfate/magnesium citrate provides a useful option in the preparation of the colon and rectum in adults, adolescents and children undergoing any diagnostic procedure (e.g. colonoscopy or x-ray examination) requiring a clean bowel and/or surgery. Oral sodium picosulfate/magnesium citrate acts locally in the colon as both a stimulant laxative, by increasing the frequency and the force of peristalsis (sodium picosulfate component), and an osmotic laxative, by retaining fluids in the colon (magnesium citrate component), to clear the colon and rectum of faecal contents. It is not absorbed in any detectable quantities. Sodium picosulfate is a prodrug: it is hydrolyzed by bacteria in the colon to the active metabolite 4,4'-dihydroxydiphenyl-(2-pyridyl)methane. Sodium picosulfate/magnesium citrate may be associated with a dehydrating effect, as evidenced by a reduction in bodyweight and increased haemoglobin levels; some at-risk patients may experience postural hypotension and older patients may require additional electrolytes. In three large (n >100), randomized, single-blind clinical studies, two sachets of oral sodium picosulfate/magnesium citrate was at least as effective as oral magnesium citrate 17.7 or 35.4 g, or oral polyethylene glycol 236 g as a colorectal cleansing agent in adult patients undergoing a double-contrast barium enema procedure. In contrast, sodium picosulfate/magnesium citrate was less effective than a sodium phosphate enema preparation in two studies in patients undergoing flexible sigmoidoscopy. A similar number of patients receiving two sachets of sodium picosulfate/magnesium citrate or two 45 mL doses of oral sodium phosphate the day before a double-contrast barium enema procedure achieved satisfactory barium coating and none/minimal faecal residue in one study. However, the data from three of these studies should be interpreted with caution because the administrative regimens used differed from that recommended. In children and adolescents, sodium picosulfate/magnesium citrate was significantly more effective as a colorectal cleansing agent than oral bisacodyl 0.01 or 0.02 g plus a sodium phosphate enema preparation in a randomized, single-blind study; dosages were adjusted for age in this study. Oral sodium picosulfate/magnesium citrate is generally well tolerated in adult patients undergoing various investigational colorectal procedures. Adverse events were generally mild to moderate in intensity and mainly gastrointestinal in nature (e.g. abdominal cramps/pain, nausea); other common treatment-emergent adverse events included disturbance of daily activity, headache and sleep disturbance. This combination is at least as well tolerated as oral sodium phosphate or oral polyethylene glycol, with moderate/severe nausea and vomiting occurring less frequently in sodium picosulfate/magnesium citrate recipients than in those receiving oral sodium phosphate, and abdominal bloating/pain and nausea developing less often with sodium picosulfate/magnesium citrate than polyethylene glycol therapy. The incidence of abdominal pain and sleep disturbance in sodium picosulfate/magnesium citrate versus oral magnesium citrate recipients was similar in one study, but significantly lower with sodium picosulfate/magnesium citrate in another. While the incidence of most adverse events was similar in recipients of sodium picosulfate/magnesium citrate and a sodium phosphate enema preparation, more patients receiving sodium picosulfate/magnesium citrate reported moderate/severe flatulence, incontinence and sleep disturbance, and more patients receiving the enema preparation reported rectal soreness. The tolerability profile of sodium picosulfate/magnesium citrate in patients aged >70 years is reportedly similar to that in patients aged <70 years. Abdominal pain also occurred less frequently with sodium picosulfate/magnesium citrate than with oral bisacodyl plus a sodium phosphate enema preparation in children and adolescents.

Laxantes con alto contenido en fosfatos: eficaces pero no tan seguros / Purgative with high sodium phosphate contents: efficacious but not so safe

No disponible

An oral carcinogenicity and toxicity study of senna (Tinnevelly senna fruits) in the rat.

Senna (Tinnevelly senna fruits), a known laxative derived from plants, was administered by gavage to Sprague-Dawley (Crl:CD (SD) BR) rats once daily at dose levels of 0, 25, 100 and 300 mg/kg/day for up to 104 consecutive weeks. Based upon clinical signs related to the laxation effect of senna, the highest dose (300 mg/kg/day) was considered to be a maximum tolerated dose. Sixty animals per sex were assigned to the control and dose groups. Assessments included clinical chemistry, hematology, full histology (control and high-dose groups; in addition, low and mid dose: intestinal tract, adrenals, liver, kidneys, brain and gross lesions) and toxicokinetics. The primary treatment-related clinical observation was mucoid feces seen at 300 mg/kg/day. When compared to controls, animals administered 300 mg/kg/day had slightly reduced body weights, increased water consumption and notable changes in electrolytes in serum (increases in potassium and chloride) and urine (decreases in sodium, potassium and chloride). The changes in electrolytes are most likely physiologic adaptations to the laxative effect of senna. At necropsy, dark discoloration of the kidneys was observed in animals in all treated groups. Histological changes were seen in the kidneys of animals from all treated groups and included slight to moderate tubular basophilia and tubular pigment deposits. In addition, for all treated groups, minimal to slight hyperplasia was evident in the colon and cecum. These histological changes, together with the changes seen in the evaluation of clinical chemistry and urine parameters, have been shown to be reversible in a previous 13-week rat study of senna. No treatment-related neoplastic changes were observed in any of the examined organs. Based upon these data, it is concluded that senna is not carcinogenic even after daily administration for 2 years at dosages of up to 300 mg/kg/day in Sprague-Dawley rats.

Phenolphthalein and bisacodyl: assessment of genotoxic and carcinogenic responses in heterozygous p53 (+/-) mice and syrian hamster embryo (SHE) assay.

Phenolphthalein (800 and 2400 mg/kg/day by gavage and 2400 mg/kg/day by diet) and bisacodyl (800-500, 4000-2000, and 8000 mg/kg/day by gavage) were administered to 15 male and 15 female and 20 male and 20 female p53(+/-) mice respectively for 26 weeks to investigate the potential carcinogenicity of each compound. Toxicokinetic analyses confirmed systemic exposure. p-Cresidine was administered by gavage (400 mg/kg/day) and served as the positive control agent in each study. Dietary phenolphthalein reduced survival in both sexes and early deaths were attributed to thymic lymphoma. No bisacodyl-related neoplasms were observed. Regardless of route of administration to p53(+/-) mice, phenolphthalein but not bisacodyl was unequivocally genotoxic, causing increased micronuclei in polychromatic erythrocytes. In the Syrian hamster embryo (SHE) cell transformation assay, phenolphthalein caused increases in morphologically transformed colonies, thereby corroborating NTP's earlier reports, showing phenolophthalein has potential carcinogenic activity. Bisacodyl was negative in the SHE assay. Results of these experiments confirm an earlier demonstration that dietary phenolphthalein causes thymic lymphoma in p53(+/-) mice and show that (1) phenolphthalein causes qualitatively identical results in this transgenic model regardless of route of oral administration, (2) phenolphthalein shows evidence of micronucleus induction in p53(+/-) mice for up to 26 weeks, (3) phenolphthalein induced transformations in the in vitro SHE assay, and (4) bisacodyl in p53(+/-) mice induces neither drug-related neoplasm, nor micronuclei in polychromatic erythrocytes, and did not induce transformations in the in vitro SHE assay.

Lactancia y medicamentos en el dolor / Breastfeeding and drugs for pain

La lactancia materna como alimentación de forma exclusiva, se considera la mejor forma de alimentación para los recién nacidos durante los primeros seis meses de vida. Aporta proteínas, grasas, carbohidratos, vitaminas y minerales, y otros factores bioactivos que facilitan el crecimiento y desarrollo, y colaboran en la defensa contra antígenos extraños y agentes infecciosos. La OMS aconseja continuar el amamantamiento, junto con otros alimentos, al menos hasta los 2 años o bien hasta que madre o hijo lo deseen. A pesar de las ventajas reconocidas, la lactancia materna aún no ha alcanzado la implantación deseable, bien por causas justificadas en algunos casos o por escasa información sobre los posibles riesgos de los medicamentos utilizados durante este periodo tanto para el lactante como la propia lactancia. Las mamas están preparadas para la lactancia desde el 4º mes del embarazo, si bien ésta no comienza hasta que no se desarrollan una serie de cambios hormonales, que se inician unas horas después del parto, y conducen a la disminución de los niveles de progesterona plasmática, mientras que los de prolactina permanecen elevados. La composición de la leche materna no es constante, observándose variaciones según la fase de la lactancia, la hora del día , la edad gestacional a la que se tiene el niño, la fase inicial y final de la toma, por ejemplo siendo más rica en contenido graso al final. Estas variaciones enriquecen el proceso nutritivo de la lactancia natural, actualmente inimitable, inigualable e insuperable como alimento para el bebé. Se estima que el 90-99 por ciento de las madres utilizan algún medicamento durante la primera semana después del parto, por tanto es considerable considerar los riesgos que puede representar para el niño lactante. El que un medicamento se excrete por la leche materna no implica necesariamente toxicidad para el lactante, ya que tendría que alcanzar determinadas concentraciones para originar efectos adversos en el lactante; y en la mayoría de los casos los niveles plasmáticos alcanzados son de escasa relevancia clínica. No obstante, la absorción de un medicamento por medio de la lactancia, en pequeñas cantidades pero repetidas podría dar lugar a su acumulación, debido a la inmadurez del metabolismo hepático (especialmente en cuanto a los procesos de acetilación, oxidación y glucuronidación) y de la excreción renal. Hay factores maternos del niño y relacionados con el medicamento que influyen en la cantidad del fármaco que se excreta a través de la leche. Son interesantes las propiedades fisicoquímicas del medicamento: ionización (al ser la leche más ácida que el plasma, los medicamentos ligeramente básicos difunden mejor en la leche respecto a los que son ligeramente ácidos); liposolubilidad (los más liposolubles pasan mejor a la leche); peso molecular (a mayor peso del fármaco mayor dificultad para penetrar en la leche); propiedades farmacocinéticas como es la absorción intestinal, unión a proteínas plasmáticas, etc. (AU)