The outcomes of favipiravir exposure in pregnancy: a case series.

PURPOSE: As in vitro and in vivo studies reported antiviral efficacy against RNA viruses, favipiravir, a pyrazinecarboxamide derivative, has become one of the treatment options for COVID-19 in some countries including Turkey. Preclinical studies demonstrated the risk for teratogenicity and embryotoxicity. Hence, the drug is contraindicated during pregnancy. Although limited in numbers, case-based evaluations indicate that favipiravir might not be a major teratogen in human pregnancies. This study aimed to present and analyze the outcomes of favipiravir exposure during pregnancy. METHODS: In this case series, the outcomes of nine pregnancies that were referred to the Teratology Information Service of Dokuz Eylul University Faculty of Medicine, Department of Medical Pharmacology between 01 April 2020 and 30 November 2021 were retrospectively evaluated. RESULTS: One spontaneous abortion, two elective terminations, one preterm live delivery and five term live deliveries were detected. The premature newborn was reported dead on the 5th day of neonatal intensive care unit admission. Physiological jaundice and transient respiratory distress were recorded in two term infants. One term infant was antenatally diagnosed with renal pelviectasis, but the findings resolved postnatally without requiring intervention. CONCLUSION: The data indicate that favipiravir is not likely to be a major teratogen. Yet, it is not possible to draw a definite conclusion due to methodological limitations. Favipiravir exposures during pregnancy should be followed up closely and the outcomes should be reported consistently.

Educational intervention to improve appropriate digoxin therapeutic drug monitoring: a quasi-experimental study.

OBJECTIVES: Our previous retrospecive study evaluating the appropriateness of serum digoxin concentration (SDC) measurements revealed errors in the timing of blood specimen collection in 98% of the tests. The aim of this study is to evaluate the appropriateness of the SDC measurements and the factors involved in inappropriate test-ordering, after training health personnel in digoxin therapeutic drug monitoring. METHODS: This is a training-based quasi-experimental study. The residents and nurses of the Cardiology Clinic were trained first in December 2017, and refresher training courses were carried out every month throughout the study. The medical data of the inpatients receiving digoxin therapy were recorded prospectively, between January and December 2018. The appropriateness of the physicians' orders for SDC measurement was evaluated according to the criteria of the right indication and right timing of blood collection. The results are presented by descriptive statistics, Student's t-test and χ2 analysis. RESULTS: A total of 232 SDC tests were ordered for 121 patients (age: 71.0±12.6 years, 56.2% women). Of these orders,129 (55.6%) were considered appropriate: 205 (88.4%) for indication and 129 (62.9%) for blood collection timing. There was a significant correlation between inappropriate order for SDC test and the age of the patient, female gender, impairment of renal function tests, high levels of serum BNP and the number of medications used (P<0.005). CONCLUSIONS: Approximately a one-half decrease in inappropriate tests compared with our previous study results imply that education has a positive effect on physician behaviour. However, physicians' concerns due to increased risk factors for the patient still play a role in inappropriate test-ordering.

Potentially inappropriate medication use in elderly patients treated in intensive care units: A cross-sectional study using 2019 Beers, STOPP/v2 Criteria and EU(7)-PIM List.

OBJECTIVE: To determine the prevalence of and the risk factors for Potentially Inappropriate Medication (PIM), the drug groups most commonly evaluated as PIMs in elderly patients in the ICUs by using 2019 Beers Criteria, STOPP version 2 (v2) Criteria and EU(7)-PIM List. The relation between mortality rate and length of ICU stay with PIMs was also examined. METHODS: This was a cross sectional study conducted on patients aged ≥65 years, treated in ICUs (n = 139) between June 8, 2020, and January 11, 2021. Patients' demographic characteristics, clinical data and laboratory findings about the drugs used were collected prospectively. PIMs were evaluated according to each of the criteria applied. Relationship of dependent and independent variables was evaluated using chi-square analysis, t-test and logistic regression analysis. P < .05 was considered statistically significant. RESULTS: The number of patients with at least 1 PIM according to three criteria was 118 (84.9%) (80.6%, 59.7%, 48.2%, Beers, STOPP/v2 and EU(7)-PIM List, respectively). In the univariate analysis, receiving renal replacement therapy and high number of drugs were the covariates that significantly affected the presence of PIM according to all three criteria (P < .05). Combined use of anxiolytics and opioids in Beers Criteria (58.3%), antipsychotics (26.6%) in STOPP/v2 Criteria, and antiarrhythmics (23.7%) in EU(7)-PIM List were the drugs that caused PIM at most. No relationship was found between the presence of PIM and mortality. The length of ICU stay was determined significantly longer in the presence of PIM according to Beers Criteria (P = .028). CONCLUSIONS: In this study, the prevalence of PIM was determined higher in elderly patients in ICU. Our results supported that 2019 Beers Criteria for ICU patients seems to be more directive in detecting PIMs and determining the prognosis. Reducing the number of drugs administered may be the first step to decrease PIMs in elderly patients in ICU and to maintain the treatment safely.

Generic drug prescribing in primary care: A nationwide analysis.

INTRODUCTION: Dissemination of generic drug (GD) use could provide significant savings on drug expenditures and contribute to the long-term sustainability of healthcare. We aimed to exhibit the nationwide trend of GD use in primary care and investigate potentially relevant drug and patient factors. METHODS: Prescriptions written by primary care physicians in Turkey between 2013 and 2016 were analysed using the National Prescribing Information System. We determined the ratio of GD prescriptions with all prescriptions in terms of quantity and cost. In addition, we analysed the use of GD in terms of demographic characteristics of the patients, the most frequently prescribed preparations and frequent indications. RESULTS: In the 4-year period, we identified 518,335,821 prescriptions, those with at least one GD constituted 54.0% (n = 786,972,813) with a total cost-share of 36.9%-37.8%. GD use was the highest in 2016 (54.4%) and lowest in 2014 (53.6%). GD prescribing was higher in women than men every year (P < .001 for each), with the highest difference in 2016 as 54.7% vs 54.0%. GD utilisation decreased as the age group increased, which was 64.0%-64.5% in <18-year-old group and 46.0%-47.1% in ≥75-year-old group. Among the top ten encountered indications, the highest and lowest GD prescribing was detected in acute tonsillitis (68.1%) and hypertension (33.9%). Metformin had the highest percentage of GD prescribing (96.1%-97.7%), whereas esomeprazole showed the lowest GD prescribing (4.5%-14.8%) among the most frequently used preparations in primary care. CONCLUSION: This study shows a modest upward trend of GD utilisation in primary care, though its share appears to be lower than expected. GD use revealed a consistent reduction towards older age groups. GDs were more likely to be prescribed for acute conditions, particularly infectious diseases.

Knowledge, opinions and attitudes of primary care physicians about generic drugs: a cross-sectional study.

BACKGROUND: Generic drug (GD) use is affected by many factors, including physicians' approach. OBJECTIVE: This study aimed to investigate the knowledge, opinions and attitudes of primary care physicians (PCPs) about GDs and potentially associated factors. METHODS: An adequately representative sample (n = 354) of PCPs was determined via stratified and simple random sample selection method in this descriptive, cross-sectional study. The research data were collected through a face-to-face 40-item survey, where the knowledge, opinions and attitudes about GDs were questioned. The prescribing percentage of GDs overall was also examined. RESULTS: The survey was completed by 305 PCPs (mean age: 49.2 ± 7.9 years; 57.4% male). The rate of correct responses about GDs was 67.6% for basic knowledge and 46.6% for the development process. The percentages of PCPs who declared that GDs were 'less efficacious', 'of lower quality' and 'less safe' than original drugs were 65.2%, 53.4% and 35.4%, respectively. More than half (60.3%) of the PCPs declared not to pay attention to whether the drug is generic while prescribing. It was observed that, as the knowledge level of the physicians increased, negative opinions and prescribing attitudes regarding the effectiveness, quality and safety of the GDs decreased. The rate of GD prescribing (51.6%) in Izmir was lower than the rest of the country (54.6%; P < 0.001). CONCLUSION: This study shows that the knowledge of PCPs about GDs is generally inadequate, which reflects negatively on their opinions and attitudes regarding the use of GDs. Educational activities can help establish awareness that GDs can be used without doubt of their effectiveness, quality and safety.

Evaluation of Legal Legislation Compliance and Readability of Clinical Trial Informed Consent Forms.

BACKGROUND: The volunteers approached for participation in a clinical trial should be given detailed and understandable information about the study through an informed consent form (ICF) before enrollment. In this study, we evaluated clinical trial files submitted to the Turkish Medicines and Medical Devices Agency (TITCK) to investigate the compliance to legal legislation and readability of ICFs as well as the factors affecting them. METHODS: This is a descriptive, cross-sectional study. We evaluated 160 ICFs in the phase II-IV clinical trial files submitted to TITCK in 2016 to determine their compliance to legislation (n = 160) and to assess their readability (n = 152) using Atesman formula. Overall compliance score was calculated. ICFs were also evaluated in terms of written format (font size, line spacing, section headings) and page count. Statistical analysis was performed with chi-square, Student's t test, analysis of variance, Mann-Whitney U, and Kruskal Wallis analysis. RESULTS: Compliance to legislation and suitability of written format of international trial ICFs were significantly higher than those of national trial ICFs. Most of the national trials were investigator initiated. Readability was low in both national and international trial ICFs where the text was longer in the latter. CONCLUSION: Results showed that researchers need easy-to-read ICF writing training that fits legal regulations.

Appropriateness of digoxin measurement in hospitalized patients.

INTRODUCTION: Measurement of serum digoxin concentrations before steady-state is reached results in a falsely low concentration, and may affect treatment safety. We evaluated the proportion of serum digoxin measurements performed before steady-state is reached and the reasons for inappropriate sampling in hospitalized patients. MATERIALS AND METHODS: Electronic medical records of patients hospitalized between January 2011 and December 2015 treated with oral digoxin, that had more than one digoxin measurement were included. Serum digoxin measurements performed before achievement of pharmacological steady state were considered as inappropriate. The chi-square and chi-square for trend tests were used to analyse the relationship between inappropriate measurements and age, gender, diagnosis, inpatient service, serum digoxin, potassium and creatinine concentrations. RESULTS: We evaluated 2065 hospital admissions for 1621 patients and 11,407 digoxin measurements. The time between consecutive measurements was 1.9 ± 2.4 days and 97% of all measurements were classified as inappropriate. There was no releationship between patient age, gender, serum creatinine concentration and inappropriate measurement. As opposed to expected, inappropriate digoxin measurement was higher when potassium concentrations were within the normal range (P = 0.025). Share of inappropriate determinations of digoxin was higher when concentrations > 2.6 nmol/L were recorded (P < 0.05). These measurements were requested most often in coronary care unit and cardiology department. CONCLUSIONS: In our study, inappropriate serum digoxin measurement was found to be very high although only one of the appropriateness criteria was evaluated. The findings reveal the need for some strategies to prevent inappropriate measurements and reduce costs.

A New Application Route of Nitrofurantoin: Preparation and Characterization of Novel Transdermal Formulations.

OBJECTIVES: Nitrofurantoin is widely used in the prophylaxis of urinary-tract infections. The aim of this study was to develop and characterize innovative transdermal formulations of nitrofurantoin, to increase the patient compliance and decrease the adverse effects such as nausea and vomiting which limit the drug use in long-term. METHODS: Nitrofurantoin loaded microemulsion, gel (hydrogel, lipogel and DMSO gel) and film formulations were prepared and characterized via several parameters. Ex-vivo drug permeation studies were performed to determine the amount of drug permeated through the rat skin. In in-vivo studies, in order to detect nitrofurantoin in urine, the selected formulations were applied to male Wistar rats transdermally. Also, skin irritation tests (transepidermal water loss and erythema) were performed. RESULTS: All nitrofurantoin loaded formulations were prepared successfully and were stable at +4°C for 3 months. 13%, 16%, 32.5%, 36.5% and 39% of drugs permeated through the rat skin in the 168th hour for hydrogel, lipogel, film, microemulsion and DMSO gel, respectively. Only with film and DMSO gel formulations, nitrofurantoin was detected in urine. Transepidermal water loss was increased compared to basal level in film type formulations (p<0.05). However, in erythema experiments there was no difference (p>0.05). CONCLUSION: There is no approved transdermal formulation of nitrofurantion on the market. Therefore, the prepared film formulations could be an alternative due to their high penetration through the rat skin, the presence of nitrofurantoin in urine and because they cause no irritation on the skin.

Short and long-term impact of pharmacovigilance training on the pharmacovigilance knowledge of medical students.

OBJECTIVES: The aim of this study was to evaluate the short and long-term impact of pharmacovigilance (PV) training on the 5th year medical students' knowledge about definitions and on the awareness of the regulatory aspects in PV. MATERIALS AND METHODS: In academic year 2010/11, the students completed structured, questionnaire before and just after training. They also completed the same questionnaire 1-year after the training. RESULTS: The students' knowledge about PV significantly increased after training in the short term (P < 0.001). However, the improvement decreased significantly in the long-term (P < 0.001). Although long-term scores were higher than the baseline score, the difference was not statistically significant. Total scores were 17.5 ± 2.0, 20.8 ± 2.0 and 18.0 ± 2.5; before, at short and long-term after the training. CONCLUSION: PV training increased the students' knowledge significantly. However, in the long-term, the impact of the training is limited. Repeated training of PV should be planned.

Rational pharmacotherapy training for fourth-year medical students.

OBJECTIVES: In this study we aimed to evaluate the impact of Rational Pharmacotherapy (RPT) course program, reinforced by video footages, on the rational pharmacotherapy skills of the students. MATERIALS AND METHODS: RPT course program has been conducted in Dokuz Eylul University School of Medicine since 2008/9. The course has been organised in accordance with World Health Organisation (WHO) Good Prescribing Guide. The aim of the course was to improve the problem solving skills (methodology for selection of the (p)ersonel-drug, prescription writing and informing patient about his illness and drugs) and communication skills of students. The impact of the course has been measured by pre/post-test design by an objective structured clinical examination (OSCE). In academic year 2010/11, to further improve OSCE score of the students we added doctor-patient communication video footages to the RPT course programme. During training, the students were asked to evaluate the doctor-patient communication and prescription on two video footages using a checklist followed by group discussions. RESULTS: Total post-test OSCE score was significantly higher for 2010/11 academic year students (n = 147) than it was for 2009/10 year students (n = 131). The 2010/11 academic year students performed significantly better than the 2009/10 academic year students on four steps of OSCE. These steps were "defining the patient's problem", "specifying the therapeutic objective", "specifying the non-pharmacological treatment" and "choosing a (drug) treatment, taking all relevant patient characteristics into account". CONCLUSIONS: The present study demonstrated that the implementation of video footages and group discussions to WHO/Good Prescribing Method improved the fourth-year medical students' performance in rational pharmacotherapy skills.

Interactions between verapamil and digoxin in Langendorff-perfused rat hearts: the role of inhibition of P-glycoprotein in the heart.

P-glycoprotein (P-gp) is expressed in tumour cells as well as normal tissues including heart. Modulation of P-gp transport in vivo may lead to increased drug penetrance to tissues with resulting increases in toxicity. We aimed to investigate the effects of P-gp on the isolated heart by digoxin infusion in the absence and presence of verapamil. The study was performed in Langendorff isolated perfused rat hearts. After a 20 min. stabilisation period with Tyrode Buffer, digoxin (125 µg/5 mL) was infused for 10 min. in the control group (n = 7). The same dose of digoxin was infused during perfusion with verapamil (1 nm) containing Tyrode Buffer (n = 8) in the study group. Outflow concentration and cardiac parameters of digoxin were measured at frequent intervals for 40 min. AUEC((0-40 min)) for left ventricular developed pressure was significantly increased in the presence of verapamil (4260 ± 39.37 mmHg min versus 4607 ± 98.09 mmHg min; 95% CI -587.7 to -105.8; p = 0.0083). The significant increases in left ventricular developed pressure were at 20, 25, 30, 35 and 40 min. AUC((0-40 min)) value for outflow digoxin concentration-time curve was significantly lower in the presence of verapamil. Verapamil increased the positive inotropic effect of digoxin, probably through the inhibition of P-gp, which effluxes digoxin out of cardiac cells.

Health profiles of methyl bromide applicators in greenhouses in Turkey

<p><b>INTRODUCTION</b>Methyl bromide is a toxic substance that has hazardous effects on human health with acute and chronic exposure. Our previous study showed that methyl bromide applicators frequently use large amounts of methyl bromide haphazardly in greenhouses in the prefectures of Narlidere and Balcova in the Aegean city of Izmir. This study aims to evaluate the health conditions of these workers.</p><p><b>MATERIALS AND METHODS</b>Our previous study showed that there are 38 methyl bromide applicators in our study area. After the informed consent of methyl bromide applicators was obtained, a questionnaire was used for a survey of demography and symptoms. Each subject was examined before and after application of the compound. Blood and urine samples were collected and stored. Blood samples were analysed for methyl bromide and bromide ion, kidney and liver function tests and lipid profile.</p><p><b>RESULTS</b>The age range of subjects was 19 to 53 years (mean age: 41 +/- 8.57). This study showed that methyl bromide applicators use large amounts of methyl bromide disregarding legal regulations and that some of them had nonspecific complaints. Subjects had been working as methyl bromide applicators for approximately 9.7 +/- 4.15 years. A total of 69.7% of methyl bromide applicators reported that they did not use protective equipment while 33.3% of them had a history of acute methyl bromide intoxication. A statistically significant relationship was found between the usage of protective equipment and the level of blood bromide ion in the blood (P <0.05).</p><p><b>CONCLUSION</b>Usage of methyl bromide, training, screening and follow-up of applicators must be rigorously controlled in accordance with national legal arrangements and international protocols. Greater efforts are required in the implementation of controls to achieve the targets set by the legal regulations and to ensure continual improvement in the limitation of the risks of this environmental hazard.</p>

Effect of subacute methyl parathion administration on the pharmacokinetics and pharmacodynamics of nifedipine in rats.

Families living in agricultural areas may submitted to repeated exposure of methyl parathion (MP) that has been widely used as an agricultural insecticide. MP inhibits cytochrome P450 enzymes and has the potential to alter pharmacokinetic profiles of therapeutic agents that are metabolized in the liver. The aim of the present study is to investigate the possibility that the increased pharmacokinetic and pharmacodynamic effects of nifedipine is due to the inhibition of the metabolism after repeated administration of low doses of MP in rats. Male rats received commercial formulation of diluted MP (1/100 LD(50) or 1/25 LD(50), n=6) or tap water (control, n=5) via gastric gavage (0.5ml) for 14 days. On the 15th day, the carotid artery and jugular vein were cannulated for measurement of cardiovascular parameters and blood sampling, respectively. Nifedipine was administered 3mg/kg via the cannula inserted in the duodenum of the rat. Subacute MP administration did not change pharmacokinetic AUC((0-240)), C(max), t(max), t(1/2)) and pharmacodynamic (mean arterial pressures and heart rates) parameters of nifedipine. These findings provide evidence that repeated exposure of low doses of commercial MP did not affect the elimination of nifedipine which might be due to the lack of inhibition of CYP3A in rats.

Erythropoietin restores bowel damage and hypoperistalsis in gastroschisis.

BACKGROUND AND PURPOSE: Despite the decreased mortality in gastroschisis (Gx), patients experience postoperative intestinal hypoperistalsis, malabsorption, and shortened bowel length. The trophic effects of recombinant human erythropoietin (rEpo) in the developing small bowel have been reported, increasing the length and height of the villi, and villous surface area. This study investigated the effects of rEpo on intestinal malfunction in the chick embryos with Gx. METHODS: Thirteen-day-old fertilized chicken eggs were used to create Gx model. Study groups included the following: group 1, control; group 2, Gx-only; group 3, Gx + 0.075% saline exchange; group 4, Gx + 10 IU rEpo exchange; group 5, Gx + 20 IU rEpo exchange. The bowels were evaluated by in vitro muscle strip technique, and the response was expressed as a percentage of the maximum carbachol-evoked contraction (Emax). In addition, parasympathetic ganglion cells per 10 plexuses and villi height were determined by light microscopy. Results were evaluated statistically by Mann-Whitney U, chi2, and Fisher's Exact test tests. RESULTS: Saline exchange had no effect on ganglion cell number (P = .63) and villi height (P = .10). In group 4, ganglion cell number was not increased (P = .82), but villi height increase was significant (P = .03). In Gx + 20 IU rEpo group, both the number of ganglia (P = .0001) and villi height (P = .002) were significantly increased. The decrease in contractility in group 2 (P = .0121) was significantly reversed by rEpo 20 IU treatment (P = .0216), no significant difference was obtained in groups 3 (P = .0809) and 4 (P = .1516) compared with group 2. CONCLUSION: These data suggest that rEpo has prokinetic effects on hypoperistalsis and restores bowel damage in Gx.

Effect of menthol on the pharmacokinetics and pharmacodynamics of felodipine in healthy subjects.

OBJECTIVES: The present study was undertaken to determine whether menthol affects the metabolism of and pharmacological responses to the calcium channel antagonist felodipine in people. METHODS: Eleven healthy subjects (ten female, one male) participated in a randomized, double-blind, two-way crossover study, comparing the kinetics and effects of a single oral dose of felodipine ER tablet (Plendil, 10 mg) with menthol (test) or placebo (reference) capsules. Ten subjects completed the study. At the beginning of the study, a 10-mg felodipine ER tablet and a 100-mg menthol or placebo capsule were given. During the 2nd, 5th and 7th hours of the study, 50, 25 and 25 mg menthol or placebo capsules were given, respectively. Blood samples and cardiovascular measurements were obtained at frequent intervals. Serum felodipine and dehydrofelodipine concentrations were determined by means of gas chromatography/mass spectrometry. RESULTS: Pharmacokinetic parameters of felodipine and dehydrofelodipine (AUC0-24, Cmax, t(max), dehydrofelodipine/felodipine AUC0-24 ratio) were not markedly changed with menthol coadministration. Only eight female subjects' cardiovascular data were included in the analysis because of technical problems during the measurements. There were no statistically significant differences in blood pressures and heart rates between the two treatments. CONCLUSIONS: We conclude that the pharmacokinetics and pharmacodynamics of felodipine were essentially unaltered by menthol.

The interaction of the diltiazem with oral and intravenous cyclosporine in rats.

This study investigated the effect of diltiazem on the bioavailability of oral and intravenous cyclosporine (CsA) in rats. While control rats received normal saline, experimental groups received 60 or 90 mg/kg diltiazem orally for 3 days. Each group divided into 2 equal groups that received a single oral dose or i.v. injection of CsA. Pharmacokinetic parameters were analyzed by nonparametric analysis of variance. Pretreatment with 60 or 90 mg/kg diltiazem decreased the area under the blood CsA concentration-time curve (AUC) of oral CsA compared to control group (54.5% and 65.5% for AUC(0-24), 57.6% and 62.2% for AUC(0-infinity), respectively, p<0.05). Mean CsA maximum concentration (Cmax) decreased from 0.4 +/- 0.1 microg/ml to 0.1 +/- 0.0 microg/mL in rats pretreated with 90 mg/kg diltiazem (p<0.05). The absolute bioavailability after oral administration (F(p.o.)) in the 60 or 90 mg/kg diltiazem groups were lower than the control group (9.6% and 8.5% versus 22.6%). Pretreatment with 90 mg/kg but not 60 mg/kg of diltiazem increased the AUC(0-infinity), elimination half-life (t1/2) of intravenous CsA (116.0%, 219.2%, respectively, p<0.05) and decreased the intravenous CsA clearence (CL(i.v.)) (62.9%, p<0.05). Diltiazem decreased the bioavailability of oral CsA, while it increased the bioavailability of intravenous CsA. One must consider this interaction when administering oral or intravenous CsA concomitantly with diltiazem.

Influence of menthol on caffeine disposition and pharmacodynamics in healthy female volunteers.

OBJECTIVES: The present study was undertaken to determine whether a single oral dose of menthol affects the metabolism of caffeine, a cytochrome P(450) 1A2 (CYP1A2) substrate, and pharmacological responses to caffeine in people. METHODS: Eleven healthy female subjects participated in a randomized, double-blind, two-way crossover study, comparing the kinetics and effects of a single oral dose of caffeine (200 mg) in coffee taken together with a single oral dose of menthol (100 mg) or placebo capsules. Serum caffeine concentrations and cardiovascular and subjective parameters were measured throughout the study. RESULTS: Co-administration of menthol resulted in an increase of caffeine t(max) values from 43.6+/-20.6 min (mean+/-SD) to 76.4+/-28.0 min ( P<0.05). The C(max) values of caffeine were lower in the menthol phase than in the placebo phase, but this effect was not statistically significant ( P=0.06). (AUC)(0-24), (AUC)(0- infinity ), terminal half-life and oral clearance were not affected by menthol. Only nine subjects' cardiovascular data were included in the analysis because of technical problems during the measurements. After caffeine, heart rate decreased in both treatment phases. The maximum decrease in heart rate was less in the menthol phase (-8.9+/-3.9 beats/min) than in the placebo phase (-13.1+/-2.1 beats/min) ( P=0.024). There were no statistically significant differences in systolic and diastolic blood pressures between the two treatments. CONCLUSIONS: We conclude that a single oral dose of pure menthol (100 mg) delays caffeine absorption and blunts the heart-rate slowing effect of caffeine, but does not affect caffeine metabolism. The possibility that menthol slows the absorption of other drugs should be considered.

Effects of amnio-allantoic fluid exchange on bowel contractility in chick embryos with gastroschisis.

BACKGROUND/PURPOSE: Intestinal damage in patients with gastroschisis is characterized by bowel wall thickening, intestinal dilatation, mesenteric shortening, and a fibrous peel. The prevention of intestinal damage in gastroschisis by amnio-allantoic fluid (AAF) exchange has been reported using histologic and macroscopic evaluation of intestines, but the effects of this treatment on bowel contractility have not been investigated. The current study was performed to determine the effect of AAF exchange on the intestinal contractility in chick embryos with gastroschisis. METHODS: Thirteen-day-old fertilized chick eggs were used. Gastroschisis was created through amnio-allantoic cavity. There were 3 study groups: control group, gastroschisis-only group, and gastroschisis-plus-exchange group. The bowels were evaluated by an in vitro muscle strip technique, and the response was expressed as a percentage of the maximum acetylcholine evoked contraction (E(max)) in each tissue obtained. Additionally, parasympathetic ganglion cells per 10 plexus at the intestinal wall were counted. Differences between groups were analyzed by analysis of variance (ANOVA) followed by Tukey-Kramer. Probabilities of less than 5% were considered significant. RESULTS: The intestines were thickened and covered by fibrous peel in the gastroschisis-only group when compared with the control group and the gastroschisis exchange group morphologically. There was a statistically significant decrease in contractility in the gastroschisis-only group compared with the control group (P <.05). It exerted 42.03 +/- 46.73% contraction of control group's E(max). This decrease in contractility was significantly reversed in the exchange group (P <.05; E(max) value of gastroschisis plus exchange group was 71.45 +/- 23.54% of control group's E(max)). Although the number of ganglia per 10 plexus was 76.7 +/- 4.3 in the control group, it was measured 28% less in the gastroschisis-only group (P <.05). There was no significant difference between the ganglion numbers of control and exchange groups. CONCLUSIONS: Prenatal AAF exchange treatment prevents decreased bowel contractility in gastroschisis. Gastroschisis does not affect intestinal ganglia morphology, but the number of ganglion cells decreases. AAF exchange prevents these functional and morphologic adverse effects of disease. By these findings the expectancy of a better clinical result in gastroschisis with intrauterine pretreatment by amniotic fluid exchange increases.