The FDA's new procedures for the use of investigational drugs in treatment

The Food and Drug Administration has established new procedures to make promising investigational drugs available for treatment of patients with immediately life-threatening or serious diseases as early in the drug development process as possible and well before general marketing begins. The purpose of this article is to inform the medical community about these new procedures and to facilitate their implementation. Examples of immediately life-threatening and serious diseases are given and the procedures that physicians should use to obtain a drug under the new regulations are described. The treatment use of zidovudine (Retrovir), while still in the investigational phase, is described as a case study. The article also summarizes the Food and Drug Administration's new procedures under which drug sponsors can charge for investigational drugs.     

Role of stereotactic biopsy in the management of transplant patients with intracranial lesions

Appropriate treatment of an intracranial lesion is based upon establishing a definitive diagnosis. CT-stereotactic biopsy procedures are highly accurate, are associated with few complications, and are usually performed only with local anesthesia. Stereotactic biopsy is the preferred method for histologically confirming the nature of an intracranial lesion in the immunocompromised patient. The mortality and morbidity approach 1 per cent, respectively. In the large reported series of stereotactic surgery for biopsy, diagnostic accuracy is over 95 per cent. Stereotactic techniques can also be used to aspirate abscesses or localize abscesses or neoplastic lesions excised by craniotomy.     

The filter properties of the arterial beds of organs in rats.

The frequency properties of arterial beds in organs were studied by temporarily ligating the renal, the gastric, the splenic or the superior mesenteric arteries of rats. Blood-pressure waves of the tail arteries were recorded before and during the ligations, and were analysed by Fourier's transformation. Their frequency spectra have been found to change profiles following specific patterns with the ligations of different arteries. The results were significant with regard to the frequency selectivities of the organic arterial beds. Such frequency properties can be clearly explained when the circulation system is viewed as an electrical circuit network in which the organic arterial beds work as filters.     

Glutamate receptors in striatum and substantia nigra: Effects of medial forebrain bundle lesions

We examined NMDA-sensitive [³H]glutamate, [³H]AMPA, [³H]kainate and metabotropic-sensitive [³H]glutamate binding sites in neostriatum and substantia nigra pars reticulata (SNr) in rats after unilateral 6-hydroxydopamine lesions of the medial forebrain bundle. One week after the lesion, NMDA, AMPA, kainate and metabotropic receptors were decreased in the ipsilateral neostriatum, whereas at three months NMDA receptors were increased while AMPA, kainate and metabotropic receptors were not changed. In the SNr at one week, only AMPA and metabotropic receptors were significantly decreased whereas three months after the lesion NMDA, AMPA and kainate binding sites were decreased. The early decrease of excitatory amino acid receptors in the striatum is likely to reflect degeneration of dopaminergic fibers, suggesting that specific subpopulations of excitatory amino acid binding sites are located on dopaminergic terminals.     

Iron deficiency anemia in children with exstrophy of the cloaca.

The clinical records of twenty-five children with exstrophy of the cloaca (EC) were retrospectively reviewed to evaluate the prevalence and the clinical characteristics of iron deficiency anemia (IDA). Five of the 25 children with EC (20 %) exhibited IDA at some point. Their ages at the time of diagnosis were between 1.9 and 13.0 years. In the four cases where IDA was thought to be related to iron malabsorption secondary to short-bowel syndrome, its treatment required longer periods of iron supplementation to correct the anemia and to restore the total body iron stores. Physicians caring for children with EC should monitor for and treat IDA as part of a comprehensive management plan.     

Expression profiling of metalloproteinases and inhibitors in cartilage

Objective   To profile the expression of all known members of the matrix metalloproteinase ( MMP ), a disintegrin and metalloproteinase with thrombospondin motifs ( ADAMTS ), and tissue inhibitor of metalloproteinases ( TIMP s) gene families in normal cartilage and that from patients with osteoarthritis (OA).
Methods   Human cartilage was obtained from femoral heads at joint replacement for either osteoarthritis or following fracture to the neck of femur. Total RNA was purified and expression of genes assayed using quantitative real-time PCR.
Results   Several members of the above gene families were regulated in OA. Genes increasing in expression in OA were: at P  < 0.001, MMP-13 , MMP-28 , ADAMTS-16 ; at P  < 0.01, MMP-9 , MMP-16 , ADAMTS-2 , ADAMTS-14 and at P  < 0.05, MMP-2 , TIMP-3 , ADAMTS-12 . Genes decreasing in expression in OA were: at P  < 0.001, MMP-1 , MMP-3 , ADAMTS-1 ; at P  < 0.01, MMP-10 , TIMP-1 , ADAMTS-9 and at P  < 0.05, TIMP-4 , ADAMTS-5 , ADAMTS-15 . Correlation analysis revealed that groups of genes across the gene families are co-expressed in cartilage.
Conclusion   This is the first comprehensive expression profile of all known MMP , ADAMTS and TIMP genes in cartilage. Patterns of expression provide a foundation on which to understand mechanisms of gene regulation in OA and potentially for refining the specificity of anti-proteolytic therapies.     

Morphine Preconditions Purkinje Cells against Cell Death under In Vitro Simulated Ischemia-Reperfusion Conditions

Background: Morphine pretreatment via activation of [delta]1-opioid receptors induces cardioprotection. In this study, the authors determined whether morphine preconditioning induces ischemic tolerance in neurons.

Methods: Cerebellar brain slices from adult Sprague-Dawley rats were incubated with morphine at 0.1-10 [mu]m in the presence or absence of various antagonists for 30 min. They were then kept in morphine- and antagonist-free buffer for 30 min before they were subjected to simulated ischemia (oxygen-glucose deprivation) for 20 min. After being recovered in oxygenated artificial cerebrospinal fluid for 5 h, they were fixed for morphologic examination to determine the percentage of undamaged Purkinje cells.

Results: The survival rate of Purkinje cells was significantly higher in slices preconditioned with morphine (>= 0.3 [mu]m) before the oxygen-glucose deprivation (57 +/- 4% at 0.3 [mu]m morphine) than that of the oxygen-glucose deprivation alone (39 +/- 3%, P < 0.05). This morphine preconditioning-induced neuroprotection was abolished by naloxone, a non-type-selective opioid receptor antagonist, by naltrindole, a selective [delta]-opioid receptor antagonist, or by 7-benzylidenenaltrexone, a selective [delta]1-opioid receptor antagonist. However, the effects were not blocked by the [mu]-, [kappa]-, or [delta]2-opioid receptor antagonists, [beta]-funaltrexamine, nor-binaltorphimine, or naltriben, respectively. Morphine preconditioning-induced neuroprotection was partially blocked by the selective mitochondrial adenosine triphosphate-sensitive potassium channel antagonist, 5-hydroxydecanoate, or the mitochondrial electron transport inhibitor, myxothiazol. None of the inhibitors used in this study alone affected the simulated ischemia-induced neuronal death.     

Ano-cutaneous flap repair for complex and recurrent supra-sphincteric anal fistula.

BACKGROUND: Suprasphincteric fistulae remain the most difficult to cure. OBJECTIVES: The purpose of this study was to evaluate the healing rate of suprasphincteric anal fistula treated by ano-cutaneous advancement flap repair, and the impact of this procedure on continence and quality of life. METHOD: Sixteen patients with complex, recurrent or chronic suprasphincteric fistulae associated with significant tissue damage (necrotizing fasciitis, keyhole deformity and anal stenosis) or who had failed previous surgical procedures were treated by ano-cutaneous flap closure. They were assessed pre and postoperatively by the treating surgeon for wound healing and fistula recurrence and later followed up by phone interview using the St Mark's Hospital incontinence score and the Perianal Disease Activity Index (PDAI) as indicators of treatment outcome. RESULTS: Fifteen patients had successful healing of their fistula with the cutaneous flap, with recurrence in only one. The most common short-term complications were minor graft site wound separation, which healed in all cases without intervention, and wound pain, which settled over time and was not associated with recurrence. Continence improved for almost 70% of the patients, with a significant reduction in St Mark's incontinence scores (t = 2.62, 15 d.f., P = 0.02). PDAI also decreased significantly (t = 7.55, 15 d.f., P < 0.001), demonstrating improvement in quality of life for most patients. CONCLUSION: Ano-cutaneous flap can achieve healing of complex and recurrent suprasphincteric anal fistula in patients who had previously failed at other forms of treatment thus improving their quality of life and continence.