De novo WNT5A-associated autosomal dominant Robinow syndrome suggests specificity of genotype and phenotype.

Robinow Syndrome (RS), a rare skeletal dysplasia syndrome, is characterized by dysmorphic features resembling a fetal face, mesomelic limb shortening, hypoplastic external genitalia in males, and renal and vertebral anomalies. Both autosomal dominant and autosomal recessive patterns of inheritance have been reported. Since the description of autosomal dominant Robinow Syndrome (ADRS; OMIM 180700) in 1969 by Meinhard Robinow and colleagues, the molecular etiology remained elusive until only recently. WNT5A was proposed to be the candidate gene for ADRS, as mutations were found in two affected families, one of those being the originally described index family. We report three families with RS caused by novel heterozygous WNT5A mutations, which were confirmed in the first family by whole exome sequencing, and in all by Sanger sequencing. To our knowledge, this is the largest number of published families with ADRS in whom a WNT5A mutation was identified. Families 1 and 2 are the first cases showing de novo inheritance in the affected family members and thus strengthen the evidence for WNT5A as the causative gene in ADRS. Finally, we propose WNT5A mutation specificity in ADRS, which may affect interactions with other proteins in the Wnt pathway.

Reacción de hipersensibilidad retardada por enoxaparina con sensibilización a otras heparinas de bajo peso molecular y no fraccionadas: tolerancia de una hirudina recombinante / Delayed hypersensitivity reaction to enoxaparin with sensitisation to other low molecular weight and unfractionated heparins: tolerance to a recombinant hirudin

La administración de heparinas no fraccionadas (HNF) o de heparinas de bajo peso molecular (HBPM) pueden ocasionar una reacción eccematosa no necrótica en el lugar de la inyección, mediada por un mecanismo de hipersensibilidad retardada. Se describe el caso de una mujer de 38 años que tras sufrir dos episodios de erupción cutánea abdominal relacionados con la administración de enoxaparina, presentó una prueba de provocación subcutánea con desirudina, una nueva hirudina recombinante, negativa. En aquellos pacientes que presenten sensibilización a heparinas, sobre todo cuando es múltiple, a HNF y a HBPM, caso de precisar coagulación urgente y a la espera de las pruebas alérgicas, las hirudinas recombinantes pueden constituir una alternativa segura (AU)

Availability of antidotes at acute care hospitals in Ontario.

BACKGROUND: Acutely poisoned patients sometimes require immediate treatment with an antidote, and delays in treatment can be fatal. We sought to determine the availability of 10 antidotes at acute care hospitals in Ontario. METHODS: Mailed questionnaire with repeated reminders to pharmacy directors at all acute care hospitals in Ontario. RESULTS: Responses were obtained from 179 (97%) of 184 hospitals. Only 9% of the hospitals stocked an adequate supply of digoxin immune Fab antibody fragments, a life-saving antidote for patients with severe digoxin toxicity, whereas most of the hospitals stocked sufficient supplies of ipecac syrup (88%) and flumazenil (92%), arguably the least crucial antidotes in the survey. Only 1 hospital stocked adequate amounts of all 10 antidotes. Certain hospital characteristics were associated with adequate antidote stocking (increased annual emergency department volume, teaching hospital status and designation as a trauma centre). Conversely, antidote supplies were particularly deficient at small hospitals and, paradoxically, geographically isolated facilities (those most reliant on their own inventory). The cost of antidotes correlated only weakly with stocking rates, and many examples of excessive antidote stocking were identified. INTERPRETATION: Most acute care hospitals in Ontario do not stock even minimally adequate amounts of several emergency antidotes, possibly jeopardizing the survival of an acutely poisoned patient. Much of this problem could be rectified at no additional cost by reducing excessive stock of expensive antidotes and redistributing the resources to acquire deficient antidotes.

Efficacy and safety of desensitization to allopurinol following cutaneous reactions.

OBJECTIVE: To evaluate the long-term efficacy and safety of slow oral desensitization in the management of patients with hyperuricemia and allopurinol-induced maculopapular eruptions. METHODS: A retrospective evaluation of an oral desensitization regimen using gradual dosage-escalation of allopurinol in 32 patients (30 with gout and 2 with chronic lymphocytic leukemia) whose therapy was interrupted because of a pruritic cutaneous reaction to the drug. RESULTS: Twenty-one men and 11 women with a mean age of 63 years (range 17-83 years), a mean serum urate level of 618 micromoles/liter (range 495-750) (or, mean 10.4 mg/dl [range 8.3-12.6]), and a mean serum creatinine level of 249 micromoles/liter (range 75-753) (or, mean 2.8 mg/dl [range 0.8-8.5]) were studied. Desensitization failed in 4 patients because of unmanageable recurrent rash. Twenty-eight patients completed the desensitization procedure to a target allopurinol dosage of 50-100 mg/day, 21 without deviation from the protocol for a mean of 30.5 days (range 21-56 days) and 7 requiring dosage adjustments because of a recurrent rash over 53.8 days (range 40-189 days). Seven of these 28 patients developed late cutaneous reactions 1-20 months postdesensitization, 4 responding to dosage modification and 3 discontinuing the drug. Twenty-five of the 32 patients (78%) continued to take allopurinol; their mean duration of followup was 32.6 months (range 3-92 months) and the mean postdesensitization serum urate level was 318 micromoles/liter (range 187-452) (or, mean 5.3 mg/dl [range 3.0-7.5]). CONCLUSION: The study confirms the long-term efficacy and safety of slow oral desensitization to allopurinol in patients with maculopapular eruptions, particularly in those with gout, who cannot be treated with uricosurics or other urate-lowering drugs. Although pruritic skin eruptions may recur both during and after desensitization, most of these cutaneous reactions can be managed by temporary withdrawal of allopurinol and dosage adjustment.

Cytokine-mediated down-regulation of CYP1A1 in Hepa1 cells.

The activation of host defense mechanisms down-regulates microsomal cytochrome P450 in cell culture, humans, and animals. Investigation into various aspects of this effect using in vivo models has yet to define clearly the role that cytokines play in this phenomenon. The mechanism of down-regulation by immunostimulants, such as lipopolysaccharide (LPS), is explored with an in vitro model, utilizing a murine hepatoma (Hepa1) and a murine macrophage (IC-21) cell line. It is hypothesized that down-regulation of P450 activity by immunostimulants involves the activation of immune cells and the subsequent release of cytokines, such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha). The effects of immunostimulation on P450 activity are assessed by ethoxyresorufin O-dealkylase, an assay that measures CYP1A activity in Hepa1 cells. Initial studies demonstrated that LPS added directly to hepatoma cells had no effect on the levels of CYP1A1 activity. In contrast, a significant down-regulation in CYP1A1 activity occurred when hepatoma cells were incubated with monocyte conditioned medium obtained by incubating LPS with IC-21 cells. When pentoxifylline, a TNF-alpha synthesis inhibitor, was co-administered with LPS to macrophages, the down-regulation of CYP1A1 activity was prevented. The direct administration of murine recombinant TNF-alpha to hepatoma cells resulted in a down-regulation of CYP1A1 activity. These results implicated the release of TNF-alpha from macrophages as an important step in the down-regulation of CYP1A1 by LPS.

Is metronidazole teratogenic? A meta-analysis.

AIM: In order to assess whether the use of metronidazole during pregnancy is associated with a higher risk of congenital malformations, a meta-analysis was conducted. METHODS: All epidemiological studies (cohort and case-control) which estimate risk of congenital malformations after exposure to metronidazole during early pregnancy were included in the meta-analysis. To obtain a summary odds ratio, the Mantel-Haenszel method was used. A test to verify absence of heterogeneity was also performed. RESULTS: One unpublished case-control and four published cohort studies fulfilled the inclusion criteria and were not statistically heterogeneous. A summary odds ratio was calculated for metronidazole exposure during the first trimester: OR = 1.08, 95% CI: 0.90-1.29, heterogeneity test chi2 = 4.72, P = 0.32. CONCLUSIONS: This meta-analysis did not find any relationship between metronidazole exposure during the first trimester of pregnancy and birth defects.

[Changes in the pattern of opioid analgesic consumption in Spain]. / Cambios en el patrón de consumo de analgésicos opioides en España.

BACKGROUND: Data from different sources have proved an infrautilization of opioid analgesics in Spain. A descriptive study has been conducted in order to know the utilization of these drugs and changes in the pattern of use in the last few years. MATERIAL AND METHOD: To know the consume of narcotic analgesic drugs, N02A group of the Anatomic Therapeutic Classification, a search was developed in the ECOM database from the Spanish Ministry of Health. This database contains information of drug preparations prescribed throughout the National Health Care System. RESULTS: The consumption of opioid analgesics in Spain has been multiplied by 5.2 during this period. It has increased from 94.7 defined daily dose per 1,000,000 inhabitants in 1985 to 489.4 in 1994. The most consumed drug in 1994 was dihydrocodeine, followed by tramadol. The number of defined daily dose per inhabitant and day of parenteral administration have decreased during the last years. CONCLUSIONS: Availability of new analgesic opioid drugs with better pharmacokinetic profiles has contributed to an increase of their consume in Spain.

[DTP vaccine and infant sudden death syndrome. Meta-analysis]. / Vacuna DTP y síndrome de muerte súbita del lactante. Un metaanálisis.

BACKGROUND: At the beginning of 1994, five cases of sudden infant death syndrome after DTP immunization appeared in Spain. In order to study a causal relationship a meta-analysis of the different studies that assess this possibility has been conducted. METHODS: The selection criteria was epidemiological study, case-control or cohort, assessing risk of sudden infant death syndrome in immunized versus non-immunized infants or risk of sudden infant death syndrome in recently immunized infants versus immunized infants beyond 30 days. Pooled risk ratios were calculated from adjusted risk ratios, when available, of the different studies, by a meta-analysis according the method described by Greenland. RESULTS: One cohort and four case-control studies were selected. Pooled risk ratio for immunized versus non-immunized infants was 0.67 (95% CI = 0.60-0.75). When comparing risk of sudden death syndrome in up to 30 days immunized infants versus more than 30 days immunized infants, the pooled risk ratio was 1.00 (95% CI = 0.84-1.20). CONCLUSIONS: DTP-immunization does not seem to increase the risk of sudden infant death syndrome. The risk of sudden infant death syndrome is not greater in the first thirty days following immunization. These data indicate a lack of association between DTP immunization and sudden infant death syndrome.

Management considerations to implementing pharmaceutical care.

Progressing towards the goal of PC requires a fundamental change to pharmacy practice. Strong leadership and management skills will be needed to facilitate this change. Even with enthusiastic and capable staff, implementation of the PC model will require considerable effort. Changes to the department's mission statement and organizational structure will be required. From this beginning, an action plan for the department can be developed. This plan includes the training of individuals and/or recruiting the necessary personnel. An ongoing education program, as well as determining the value of your service, is required. With successful implementation the PC model will lead to the acceptance of the pharmacist's role as the person responsible for identifying, preventing, and resolving drug-related problems.

The effect of food or sucralfate on the bioavailability of S(+) and R(-) enantiomers of ibuprofen.

This randomized, multiple cross-over pharmacokinetic study was undertaken to determine if food or sucralfate alter the bioavailability of the active S(+) enantiomer of ibuprofen. Eleven healthy adult male volunteers were given three single 600-mg doses of ibuprofen (separated by 1 week) administered either in a fasting state, after a standardized breakfast, or with sucralfate 1 g. The main outcome measures were area under the concentration (AUC), maximum peak plasma concentration (Cmax), and time to reach peak concentration (tmax) for total, S(+), and R(-) enantiomer serum ibuprofen levels, drawn up to 10 hours after dosing. The AUC for R(-) ibuprofen was significantly lower than S(+) ibuprofen in all three treatment groups. The treatments had no different effects on AUC for S(+), R(+), or total ibuprofen. There was no difference in the ratio of S(+):R(-) enantiomers across different treatment groups, but the intersubject variability was significant (P < .05). The S(+) ibuprofen Cmax was greater than the R(-) ibuprofen Cmax for all treatment groups (P < .05). Sucralfate reduced the peak concentration of both S(+) and R(-) enantiomers when compared with fasting (P < .05). There was a slight but nonsignificant increase in the mean time to achieve peak concentration of both S(+) and R(-) enantiomers. Neither food nor sucralfate has a significant effect on ibuprofen enantiomer pharmacokinetics, but interindividual variability contributes significantly to the variability of enantiomer bioavailability.

Desensitization to allopurinol in patients with gout and cutaneous reactions.

PURPOSE: To determine the efficacy and safety of slow oral desensitization in the management of allopurinol-related pruritic cutaneous eruptions. PATIENTS AND METHODS: Nine patients with renal insufficiency and chronic tophaceous gouty arthritis, who had to interrupt their allopurinol therapy because of an allergic-type pruritic maculopapular eruption, were enrolled in an allopurinol oral desensitization protocol using a schedule of gradually increasing doses. RESULTS: Cautious reinstitution of allopurinol was successfully accomplished in all nine patients, but four individuals required dose adjustment because of development of a mild, recurrent, macular rash early during the protocol at allopurinol doses of less than or equal to 5 mg/d. Transient, postdesensitization cutaneous reactions occurred in two patients, one of whom also had an early rash. CONCLUSION: Oral desensitization to the minor rashes induced by allopurinol is a feasible and acceptably safe approach to therapy, particularly for those with renal insufficiency in whom no substitute urate-lowering drug is available.

Single-dose pefloxacin pharmacokinetics and metabolism in patients undergoing continuous ambulatory peritoneal dialysis (CAPD).

Seven adult patients on continuous ambulatory peritoneal dialysis (CAPD) received one dose of pefloxacin, a novel quinolone antibiotic, orally and intravenously on two separate occasions to characterize the pharmacokinetics and metabolism of the drug. Concentrations of both pefloxacin and its active metabolite N-desmethyl-pefloxacin (norfloxacin) were measured in serum and dialysate by HPLC. Half-life, total body clearance and peritoneal clearance were determined. The overall elimination half-life was 19.9h. Relative to the IV dose the bioavailability following oral administration of pefloxacin was 76%. The mean serum and dialysate concentrations were similar up to 24 h after the oral or IV dose. After a 6-h dwell time the dialysate concentration of pefloxacin was 2.24 mg/L which is above the MIC90 for most bacteria responsible for peritonitis in CAPD patients. The peritoneal clearance of pefloxacin averaged 2.5 mL/min. Serum concentrations of the metabolite norfloxacin were less than 0.5 mg/L during the 24 h study period. We conclude that pefloxacin might be equally effective in the treatment of peritonitis of CAPD after oral or IV administration. Since the peritoneal clearance contributes insignificantly to the elimination of pefloxacin during CAPD, the proposed maintenance regimen of an oral or IV 400 mg dose/day seems to be a reasonable therapy for infections in CAPD patients.

Childhood deaths from toy balloons.

We describe four children who died of suffocation by rubber balloons in Canada between 1983 and 1988. In the United States, at least 121 children have died in a similar manner in the 15 years between 1973 and 1988 according to a report by the US Consumer Product Safety Commission. Although the highest mortality occurred among infants, 30 (25%) of the 121 deaths occurred in children 6 years of age or older. Balloons account for 43% of the approximately 15 childhood deaths related to children's products that are documented each year by the Consumer Product Safety Commission. Toy rubber balloons are thus the leading cause of pediatric choking deaths from children's products. Preventive efforts should be directed toward a ban on this type of balloon and the development of safer alternatives. Meanwhile, public information campaigns should alert parents, physicians, and policymakers to the dangers of toy rubber balloons.

Bioavailability of iron in oral ferrous sulfate preparations in healthy volunteers.

The bioavailability of iron in five ferrous sulfate preparations was studied in 10 healthy male volunteers. The preparations were an oral solution, two types of film-coated tablets and two types of enteric-coated tablets. Blood samples were drawn hourly from 8 am to 6 pm on the day before each study day to assess baseline serum iron concentrations and on the study day. Spectrophotometry was used to measure the serum iron concentrations. The area under the curve (AUC), the maximum concentration and the time to achieve the maximum concentration were compared by analysis of variance. The enteric-coated preparations resulted in AUCs less than 30% of the AUC for the oral solution. The two film-coated products produced AUCs essentially equivalent to that of the oral solution. We conclude that the bioavailability of iron in the enteric-coated preparations was low, relative to that of the film-coated products and the oral solution, and that these products should not be considered interchangeable.

[Primary ventricular fibrillation. Clinical features and prognostic significance]. / Fibrilación ventricular primaria. Características clínicas y significado pronóstico.

The objective of this study was to evaluate the clinic conditions and the prognosis of patients with primary ventricular fibrillation (PVF) as complication of acute myocardial infarction. We retrospectively analyzed 1,120 patients admitted in Coronary Care Unit within 12 hours of onset of symptoms. PVF (not associated with significative heart failure or shock and occurred within 48 hours of onset of symptoms) occurred in 62 patients (5.53%). The frequency of PVF was highest in patients admitted in the first hours after infarction (p = 0.01) and the inferior localization (p = 0.001). Cigarette smoking was identified as strong independent risk factor for ventricular fibrillation (p = 0.009; relative risk 1.945). A statistically significant excess of pericarditis (p = 0.002), ventricular tachycardia (p = 0.004), atrioventricular block (second-third degree) (p = 0.001) and moderate degree of heart failure (p = 0.003), was found in patients with PVF. The occurrence of PVF was not associated to a significantly higher in hospital mortality rate than that observed in reference group (without ventricular fibrillation) (12.90 vs 14.36%). In the long-term survival at 5 years in patients with PVF, who are discharged alive, was 87.82% vs 80.58% in control group. We conclude: 1. Patients with PVF had more complications rate than among those without it. 2. PVF isn't a marker of increase in hospital death rate. 3. PVF by itself does not indicate an adverse long-term prognosis.

Trimethoprim-sulfamethoxazole pharmacokinetics during continuous ambulatory peritoneal dialysis (CAPD).

Ten adult patients on continuous ambulatory peritoneal dialysis (CAPD) received one dose of trimethoprim-320 mg (TMP) and sulfamethoxazole 1600 mg (SMX) orally (p.o.), intravenously (i.v.), and intraperitoneally (i.p.) on three separate occasions to characterize the pharmacokinetics of both drugs. Concentrations of both TMP and SMX were measured in serum and dialysate by HPLC to 48 h. Half-life, total body clearance (TBC), and peritoneal clearance (PCl) were determined. The mean half-life of TMP was 28 h, while for SMX it was 12.5 h. Relative to the i.v. dose, the bioavailability following oral administration for TMP was 98% and 87% for SMX. Intraperitoneal bioavailability was 73% for TMP and 65% for SMX after a 4-h dwell. After 24 h, regardless of the route of administration, less than 3% of TMP and less than 6% of SMX appeared in dialysate. We conclude that peritoneal losses contribute insignificantly to TMP/SMX elimination during CAPD.