Compliance and adverse drug reactions: a prospective study with ethinylestradiol using continuous compliance monitoring

Summary This study examined the relationship between adverse reactions and patient compliance with ethinylestradiol at 40 g twice daily versus 20 g four times daily. In a randomized study 61 female patients with primary- infertility were prescribed the drug twice daily (n = 31) or four times daily (n = 30). Ethinylestradiol was administered for 7 days before the sperm cervical mucus penetration-test was performed for hormonal standardization of the cervical mucus quality. Drug compliance was measured by continuous monitoring using the Medication Event Monitoring System. Two parameters were evaluated: percentage of prescribed doses taken (administration compliance) and adherence to the prescribed dose schedule (regimen compliance, number of days with two or four dosing events recorded). Adverse drug reactions were assessed using a standardized questionnaire. Fourty-four women experienced side effects, of which 81% were rated by patients as being mild. Patient compliance was higher with the twice daily than with the four times daily regimen: 85% versus 65% prescribed doses taken (P<0.05). There was no significant difference in compliance comparing patients with and without adverse reactions (82% versus 72%, respectively), but compliance was lower and more irregular with at least 3 versus one or two adverse reactions reported: 54% versus 84% in administration compliance and 31% versus 58% in regimen compliance (P<0.05). Compliance was also lower in patients with nausea and vomiting than in those without these symptoms, 59% versus 91% and 34% versus 66% (P<0.005), respectively, and lower with moderate or severe compared to mild side effects; 48% versus 85% and 25% versus 59% (P<0.005). Thus the mere occurrence of side effects was not associated with low compliance. However, the number and nature of symptoms and their intensity as perceived by patients may have considerably influenced drug use behavior.Abbreviations ADR adverse drug reactions - SCMPT sperm cervical mucus penetration-test Prof. Dr. E. Weber died 7 December 1992     

Alternative techniques for gaining venous access. What to do when peripheral intravenous catheterization is not possible

There are a number of therapeutic options for fluid administration in patients who lack usual venous access. Ways to establish this access include limb elevation and wrapping, the application of nitroglycerin ointment to dilate veins, and blood pressure cuff inflation. Ultrasonography can also be used to delineate vascular structures. Cutdown procedures are the oldest, most direct method to reach uncommon venous sites, such as the inferior epigastric, intercostal, iliac, and lateral thoracic veins. Today, cutdown procedures are regarded as the method of last resort, and they should be performed in operating suites or similar settings. Possible complications include inadvertent arterial puncture and hemorrhage.     

Techniques for vascular access when venous entry is impossible. Route depends on urgency and the agent to be administered

When a patient requires parenteral fluid or drug administration and venous cannulation cannot be performed, consider less typical routes. Intraosseus infusions are usually more effective in children than adults, but intraosseus cannulation failure may occur in as many as 20% of patients. Intra-arterial infusions are possible if pump pressures are kept high. Hypodermoclysis (infusion into the subcutaneous tissues) can correct moderate dehydration. Administering resuscitative drugs endobronchially is usually safe and effective, although pulmonary function may be somewhat compromised. A number of drugs may be given sublingually, either by injection or topical application. Finally, the corpora cavernosa of the penis may be used for short-term, large-volume fluid administration.     

Visual cortex activation recorded by dynamic emission computed tomography of inhaled xenon 133

Regional cerebral blood flow (CBF) was studied tomographically with ¹³³Xe administered by inhalation over a 1-min period at a concentration of 10 mCi/l. A fast rotating (dynamic) single-photon emission computed tomograph with four detector heads was used, an instrument that has been found to be well suited for detecting focal ischemia. In the present study its ability to detect focal hyperemia was investigated in 13 normal subjects studied during rest and during visual stimulation. A flickering light seen with eyes open and closed, increased blood flow in the visual cortex by 35% and 22% respectively. Looking at different pictures displayed on a screen raised regional CBF by 26%. The most complex task, reading and copying a text, increased blood flow by 45%. Averaging the different tasks resulted in a mean regional CBF increase in the visual cortex of 35%. The result is comparable with that obtained by positron emission tomography. Both forms of isotope tomography offer unique possibilities for the study of brain function in health and disease, possibilities not matched by X-ray tomography. The low cost and ready availability of appropriate single-photon radionucleides (¹³³Xe and ¹²⁷Xe) are mentioned.Supported by the Danish Medical Research Council, the Danish Sclerose Association, and the Johann and Hanne Weimann Foundation.     

Metabolism of Testosterone During in Vitro Transport Across CACO-2 Cell Monolayers: Evidence for β-Hydroxysteroid Dehydrogenase Activity in Differentiated CACO-2 Cells

Testosterone has previously been used as a model compound for the determination of unstirred water layer thickness in the CACO-2 transport model. We have found, however, that testosterone is metabolized during in vitro transport across the CACO-2 cell monolayers. This suggests that testosterone is not an ideal model substance. Testosterone is metabolized to androstenedione, indicating the formation of 17--hydroxysteroid dehydrogenase by differentiated CACO-2 cells. No reverse metabolism is observed, thus androstenedione is considered superior to testosterone for determination of unstirred water layer thickness in the CACO-2 system. Permeability coefficients for testosterone and androstenedione obtained under identical transport conditions were 66 (±7) * 10 ^–6 (n = 26) and 84 (±7) * 10^–6 (n = 9) cm/sec, respectively. The unstirred water layer thicknesses at different agitation rates are determined for the CACO-2 transport model used in our laboratory utilizing androstenedione as a model compound. The system is capable of controlling the water layer thickness from about 200 to 1000 µm.     

Steady-state kinetics of imipramine in patients

Steady-state plasma level kinetics were studied in 76 patients given imipramine (IP) 150 to 225 mg/day for 2–5 weeks. IP was given in three divided doses at 8.00 a.m., 1.00 p.m. and 5.00 p.m. Plasma concentrations of IP and its active metabolite desipramine (DMI) were determined by quantitative in situ thin-layer chromatography. The plasma levels of IP and DMI showed pronounced flucutations throughout the day with a ratio of about 2 between highest and lowest level. Patients with steady-state levels of IP and/or DMI below 50 g/l reached this within 1 week of treatment. Patients with higher steady-state levels reached steady-state concentrations within 2–3 weeks. There were some intraindividual fluctuations in plasma levels from week to week after steady state had been reached (coefficient of variation: 10–20%). Interindividually, the steady-state levels corrected to a dose of 3.5 mg/kg per day varied considerably: IP: 6–356 g/l, DMI: 24–659 g/l and IP+DMI: 58–809 g/l. The steady-state plasma levels showed a skew distribution that became normal by logarithmic transformation. The IP/DMI ratio ranged from 0.07 to 5.5 with a median value of 0.47. Compared to data from amitriptyline treated patients the IP/DMI ratios had significantly lower median value and larger variation than the corresponding plasma level ratios of amitriptyline/nortriptyline. Several statistically significant differences in steady-state levels between age groups were found. For IP: Women aged 30–39 had lower levels than women aged 20–29, 40–49, and 50–59, and men aged 50–59 and 60–65; men aged 30–39 had lower levels than men aged 60–65. For DMI: Women aged 30–39 had lower levels than women aged 50–59.     

Bladder Cancer and Arsenic Exposure： Differences in the Two Populations Enrolled in A Study in Southwest Taiwan

Objective Analyses of bladder cancer mortality in the Black Foot Disease (BFD) endemic area of southwest Taiwan conducted by Morales et al. showed a discontinuity in risk at 400 μg/L arsenic in the drinking water in a stratified analysis and no discontinuity in a continuous analysis.     

E5 murine monoclonal antiendotoxin antibody in gram-negative sepsis: a randomized controlled trial. E5 Study Investigators

Context  Knowledge and understanding of gram-negative sepsis have grown over the past 20 years, but the ability to treat severe sepsis successfully has not. Objective  To assess the efficacy and safety of E5 in the treatment of patients with severe gram-negative sepsis. Design  A multicenter, double-blind, randomized, placebo-controlled trial conducted at 136 US medical centers from April 1993 to April 1997, designed with 90% power to detect a 25% relative risk reduction, incorporating 2 planned interim analyses. Setting  Intensive care units at university medical centers, Veterans Affairs medical centers, and community hospitals. Patients  Adults aged 18 years or older, with signs and symptoms consistent with severe sepsis and documented or probable gram-negative infection. Intervention  Patients were assigned to receive 2 doses of either E5, a murine monoclonal antibody directed against endotoxin (n = 550; 2 mg/kg per day by intravenous infusion 24 hours apart) or placebo (n = 552). Main Outcome Measures  The primary end point was mortality at day 14; secondary end points were mortality at day 28, adverse event rates, and 14-day and 28-day mortality in the subgroup without shock at presentation. Results  The trial was stopped after the second interim analysis. A total of 1090 patients received study medication and 915 had gram-negative infection confirmed by culture. There were no statistically significant differences in mortality between the E5 and placebo groups at either day 14 (29.7% vs 31.1%; P = .67) or day 28 (38.5% vs 40.3%; P = .56). Patients presenting without shock had a slightly lower mortality when treated with E5 but the difference was not significant (28.9% vs 33.0% for the E5 and placebo groups, respectively, at day 28; P = .32). There was a similar profile of adverse event rates between E5 and placebo. Conclusions  Despite adequate sample size and high enrollment of patients with confirmed gram-negative sepsis, E5 did not improve short-term survival. Current study rationale and designs should be carefully reviewed before further large-scale studies of patients with sepsis are conducted.      

Foix-Chavany-Marie (anterior operculum) syndrome in childhood: a reappraisal of Worster-Drought syndrome

Foix-Chavany-Marie syndrome (FCMS) is a distinct clinical picture of suprabulbar (pseudobulbar) palsy due to bilateral anterior opercular lesions. Symptoms include anarthria/severe dysarthria and loss of voluntary muscular functions of the face and tongue, and problems with mastication and swallowing with preservation of reflex and autonomic functions. FCMS may be congenital or acquired as well as persistent or intermittent. The aetiology is heterogeneous; vascular events in adulthood, nearly exclusively affecting adults who experience multiple subsequent strokes; CNS infections; bilateral dysgenesis of the perisylvian region; and epileptic disorders. Of the six cases reported here, three children had FCMS as the result of meningoencephalitis, two children had FCMS due to a congenital bilateral perisylvian syndrome, and one child had intermittent FCMS due to an atypical benign partial epilepsy with partial status epilepticus. The congenital dysgenetic type of FCMS and its functional epileptogenic variant share clinical and EEG features suggesting a common pathogenesis. Consequently, an increased vulnerability of the perisylvian region to adverse events in utero is discussed. In honour of Worster-Drought, who described the clinical entity in children 40 years ago, the term Worster-Drought syndrome is proposed for this unique disorder in children.