Bioavailability and pharmacokinetics of lorazepam after intranasal, intravenous, and intramuscular administration.

The purpose of this study was to evaluate the pharmacokinetic profile of intranasal lorazepam in comparison to currently established administration routes. Eleven healthy volunteers completed this randomized crossover study. On three occasions, each separated by a 1-week washout, subjects received a 2 mg dose of lorazepam via the intranasal, intravenous, or intramuscular route. Blood samples were collected serially from 0 to 36 hours. Noncompartmental methods were used to determine pharmacokinetic parameters. Lorazepam was well absorbed following intranasal administration with a mean (%CV) bioavailability of 77.7(11.1). Intranasal administration resulted in a faster absorption rate than intramuscular administration. Elimination profiles were comparable between all three routes. The concentration-time profile for intranasal delivery demonstrated evidence of a double peak in several subjects, suggesting partial oral absorption. Females were found to have significantly higher AUC values than males for all three delivery routes. Overall, this study demonstrated favorable pharmacokinetics of intranasal lorazepam in relation to standard administration methods. Intranasal delivery could provide an alternative, noninvasive delivery route for lorazepam.

Localization of the gene for familial laryngeal abductor paralysis to chromosome 6q16.

BACKGROUND: Vocal fold paralysis is a common cause of neonatal stridor. Although it is usually classified as idiopathic or iatrogenic in origin, a small subset of patients have a family history of this disorder, indicating a possible genetic cause. OBJECTIVE: To identify the genetic locus of the gene that causes familial laryngeal abductor paralysis. DESIGN: A standard nonorganic protocol was used to extract DNA from whole-blood samples. The DNA samples were quantified by DNA fluorometry, and the concentration of all samples was standardized at 40 ng/microL. A pooled DNA strategy was used to facilitate rapid polymerase chain reaction screening of markers in the Weber v8.0 genome screening set. Polymerase chain reaction screening of individual DNA samples was performed using possible linked markers initially identified as having an allele that appeared with a higher incidence in the affected DNA pools. Statistical analysis of possible linkage was performed using the LINKAGE 5.1 set of linkage analysis computer programs. SUBJECTS: A family in which a form of familial laryngeal abductor paralysis segregates was ascertained. Whole blood samples were drawn from 40 participating individuals within this family after the subjects' fully informed consent was obtained. RESULTS: Initial screening of the pooled DNA specimens revealed a band pattern for D6S1021 on chromosome 6q16, indicating an allele with a higher incidence in the affected vs the nonaffected pool. Two-point analysis of individual allele patterns confirmed linkage to D6S1021 with an lod score of 3.86 (straight theta = 0.0) at a penetrance value of 0.8. Haplotype analysis with flanking markers defined a 5-centiray critical region between D6S283 and AFMA047YG1. CONCLUSION: An autosomal dominant form of familial laryngeal abductor paralysis is linked to a 5-centiray region on chromosome 6q16 surrounding D6S1021.

Tracheal agenesis: diagnosis and management.

Tracheal agenesis (TA) is a rare congenital anomaly that typically has fatal consequences. Its rarity, lack of prenatal symptoms, and emergent presentation usually lead to a failure to arrive at the correct diagnosis and manage the airway properly before the onset of irreversible cerebral anoxia. We report the case history of an infant born with immediate respiratory failure who was diagnosed with tracheal agenesis. The clinical features, embryology, classification schemes and surgical management are discussed with the hope that increased awareness and earlier diagnosis may lead to better chances of survival for affected individuals.

Age-related mitochondrial DNA mutations in the human larynx.

OBJECTIVE: To determine whether age-related mitochondrial DNA mutations occur in the human larynx. STUDY DESIGN: Genetic study of cadaveric larynx specimens. METHODS: Vocal fold mucosa, thyroarytenoid muscle, and cricoarytenoidjoint tissue were harvested from 13 fresh postmortem larynges (age range, 2 d-82 y). DNA was extracted from each sample, and the polymerase chain reaction (PCR) was used to amplify a target DNA sequence resulting from the common age-associated, 4977-base-pair (bp) mitochondrial DNA deletion. PCR products were visualized by agarose gel electrophoresis. Automated sequencing determined the sequence of identified PCR products. SUBJECTS: Thirteen cadaveric larynges were obtained through the University of Kentucky Medical Center (Lexington, KY). Specimens from patients with a history of head and neck cancer, previous laryngeal trauma, or surgery were excluded. RESULTS: Strongly positive bands were identified in samples from three individuals. Weaker bands were seen in samples from four other samples. No band was noted from the two pediatric larynges. Different band patterns were seen among the three different tissue sites in the larynges with positive PCR products, but no consistent pattern was seen. Sequencing of the identified PCR products from selected samples confirmed that they were products of the age-associated, 4977-bp mitochondrial DNA deletion. CONCLUSIONS: An age-associated mitochondrial DNA deletion was detected in several post-mortem human larynges. Its presence seemed to increase in appearance with age. In the larynges in which the deletion occurred, there were individual regional differences in the occurrence of the deletion, but no consistent pattern was noted across all individuals who carried the deletion.

Otolaryngologic aspects of oral-facial-digital syndrome.

The oral-facial-digital (OFD) syndromes are a heterogeneous group of hereditary disorders which have in common the findings of oral abnormalities, facial dysmorphism, and hand/feet malformations. We report the case history of an 18-month-old male with cerebellar cysts, hydrocephalus, tongue hamartomas, and polydactyly. These findings are most consistent with OFD VI. The clinical features of eight different types of OFD are discussed, with particular attention to the characteristics of the most interest to the otolaryngologist.

Variations in end-expiratory pressure during partial liquid ventilation: impact on gas exchange, lung compliance, and end-expiratory lung volume.

STUDY OBJECTIVES: To determine the effects of different levels of positive end-expiratory pressure (PEEP) during partial liquid ventilation (PLV) on gas exchange, lung compliance, and end-expiratory lung volume (EELV). DESIGN: Prospective animal study. SETTING: Animal physiology research laboratory. SUBJECTS: Nine piglets. INTERVENTIONS: Animals underwent saline solution lavage to produce lung injury. Perflubron was instilled via the endotracheal tube in a volume estimated to represent functional residual capacity. The initial PEEP setting was 4 cm H(2)O, and stepwise changes in PEEP were made. At 30-min intervals, the PEEP was increased to 8, then 12, then decreased back down to 8, then 4 cm H(2)O. MEASUREMENTS AND RESULTS: After 30 min at each level of PEEP, arterial blood gases, aortic and central venous pressures, heart rates, dynamic lung compliance, and changes in EELV were recorded. Paired t tests with Bonferroni correction were used to evaluate the data. There were no differences in heart rate or mean BP at the different PEEP levels. CO(2) elimination and oxygenation improved directly with the PEEP level and mean airway pressure (Paw). Compliance did not change with increasing PEEP, but did increase when PEEP was lowered. EELV changes correlated directly with the level of PEEP. CONCLUSIONS: As previously reported during gas ventilation, oxygenation and CO(2) elimination vary directly with PEEP and proximal Paw during PLV. EELV also varies directly with PEEP. Dynamic lung compliance, however, improved only when PEEP was lowered, suggesting an alteration in the distribution of perflubron due to changes in pressure-volume relationships.

Cervical vertebral anomalies in patients with anomalies of the head and neck.

Congenital head and neck anomalies can occur in association with vertebral anomalies, particularly of the cervical vertebrae. While the former are easily recognized, especially when part of a syndrome, the latter are often occult, thereby delaying their diagnosis. The presence of vertebral anomalies must be considered in pediatric patients with head and neck abnormalities to expedite management of select cases and to prevent neurologic injury. We present our experience with 5 pediatric patients who were referred to the Department of Otolaryngology-Head and Neck Surgery at the University of Iowa with a variety of syndromic anomalies of the head and neck. Each patient was subsequently also found to have a vertebral anomaly. The relevant embryogenesis of the anomalous structures is discussed, with highlighting of potential causes such as teratogenic agents and events and germ-line mutations. A review of syndromes having both head and neck and vertebral anomalies is presented to heighten awareness of otolaryngologists evaluating children with syndromic disorders. Finally, the findings on radiographic imaging studies, particularly computed tomography, are discussed to facilitate the prompt diagnosis of vertebral anomalies.

Familial laryngeal paralysis.

Vocal fold paralysis (VFP) is the second most frequent cause of congenital stridor. Although often due to birth trauma, infection, and brainstem abnormalities, most cases are idiopathic. Infrequently, a family history of VFP is elicited, identifying a role for genetic factors in laryngeal function. This study describes a family in which an autosomal dominant form of familial laryngeal abductor paralysis segregates. The typical physical findings, diagnostic and therapeutic considerations, and possible molecular mechanisms of this disorder are discussed in detail.