Quantitative imaging and sigmoidoscopy to assess distribution of rectal microbicide surrogates.

Understanding the distribution of microbicide and human immunodeficiency virus (HIV) within the gastrointestinal tract is critical to development of rectal HIV microbicides. A hydroxyethylcellulose-based microbicide surrogate or viscosity-matched semen surrogate, labeled with gadolinium-DTPA (diethylene triamine pentaacetic acid) and 99mTechnetium-sulfur colloid, was administered to three subjects under varying experimental conditions to evaluate effects of enema, coital simulation, and microbicide or semen simulant over 5 h duration. Quantitative assessment used single photon emission computed tomography (SPECT)/computed tomography (CT) and magnetic resonance imaging (MRI) imaging, and sigmoidoscopic sampling. Over 4 h, radiolabel migrated cephalad in all studies by a median (interquartile range) of 50% (29-102%; P<0.001), as far as the splenic flexure (approximately 60 cm) in 12% of studies. There was a correlation in concentration profile between endoscopic sampling and SPECT assessments. HIV-sized particles migrate retrograde, 60 cm in some studies, 4 h after simulated ejaculation in our model. SPECT/CT, MRI, and endoscopy can be used quantitatively to facilitate rational development of microbicides for rectal use.

Treatment in Kenyan rural health facilities: projected drug costs using the WHO-UNICEF integrated management of childhood illness (IMCI) guidelines.

Guidelines for the integrated management of childhood illness (IMCI) in peripheral health facilities have been developed by WHO and UNICEF to improve the recognition and treatment of common causes of childhood death. To evaluate the impact of the guidelines on treatment costs, we compared the cost of drugs actually prescribed to a sample of 747 sick children aged 2-59 months in rural health facilities in western Kenya with the cost of drugs had the children been managed using the IMCI guidelines. The average cost of drugs actually prescribed per child was US$ 0.44 (1996 US$). Antibiotics were the most costly component, with phenoxymethylpenicillin syrup accounting for 59% of the cost of all the drugs prescribed. Of the 295 prescriptions for phenoxymethylpenicillin syrup, 223 (76%) were for treatment of colds or cough. The cost of drugs that would have been prescribed had the same children been managed with the IMCI guidelines ranged from US$ 0.16 per patient (based on a formulary of larger-dose tablets and a home remedy for cough) to US$ 0.39 per patient (based on a formulary of syrups or paediatric-dose tablets and a commercial cough preparation). Treatment of coughs and colds with antibiotics is not recommended in the Kenyan or in the IMCI guidelines. Compliance with existing treatment guidelines for the management of acute respiratory infections would have halved the cost of the drugs prescribed. The estimated cost of the drugs needed to treat children using the IMCI guidelines was less than the cost of the drugs actually prescribed, but varied considerably depending on the dosage forms and whether a commercial cough preparation was used.

PIP: This study evaluated the impact of the integrated management guidelines of childhood illness (IMCI) developed by the WHO and UN Children's Fund on the treatment cost in Kenya. To determine the impact of the guidelines, a comparison was made of the cost of drugs actually prescribed to 747 sick children aged 2-59 months in rural facilities with the treatment cost had the children been managed following the IMCI guidelines. The study found that the estimated cost of drugs required to treat children following the IMCI guidelines was lower than the cost of the drugs actually prescribed in ill children. The average cost of drugs actually prescribed for every sick child was US$0.44. Antibiotics were the most expensive component, with phenoxymethylpenicillin syrup responsible for 59% of the total cost of prescribed drugs. The cost of medications that would have been prescribed had the children been treated using the guidelines ranges from US$0.16 to US$0.39 per patient. Managing cough and colds with antibiotics is not recommended in the IMCI guidelines, thus, compliance to guidelines would have reduced the treatment cost to one half the cost of drugs actually prescribed.

Thyroid test abnormalities in traumatic brain injury: correlation with neurologic impairment and sympathetic nervous system activation.

Acute illness is well known to affect thyroid function, but there are few studies correlating the severity of the underlying medical problem with indexes of thyroid function and little is known about its cause. Traumatically brain-injured patients were selected because they were a relatively homogeneous, previously healthy group with a condition whose severity was readily quantifiable. In 66 such patients, the relationships between changes in thyroid function tests (thyroxine, free thyroxine, triiodothyronine, reverse triiodothyronine, and thyrotropin levels), catecholamine and cortisol concentrations measured on admission and again four days after the accident, and neurologic function assessed by the Glasgow Coma Score (GCS) were studied. Triiodothyronine and thyroxine levels fell significantly within 24 hours of injury. Four days after the accident, patients with the greatest neurologic dysfunction had the lowest triiodothyronine and thyroxine levels; significant correlations were present between the Day 4 GCS and concomitant thyroxine (r = 0.47, p less than 0.0001), free thyroxine (r = 0.32, p less than 0.02), and triiodothyronine (r = 0.50, p less than 0.0001) levels. Reverse triiodothyronine values remained unchanged throughout the study even in the most severely affected patients; the rise in thyrotropin levels was not significant (1.2 +/- 0.2 to 1.7 +/- 0.3 microU/ml, p = NS). Patients who died or remained vegetative had thyroxine and triiodothyronine levels 30 percent to 50 percent lower than those who had a good recovery (p less than 0.05). Highly significant correlations were present between Day 4 thyroxine and triiodothyronine levels and admission and Day 4 norepinephrine and epinephrine concentrations. There was no association between admission or concomitant cortisol levels and thyroid function on Day 4; treatment with high-dose dexamethasone did not influence these indexes. Thus, patients with traumatic brain injury exhibit a gradient of thyroid dysfunction that occurs promptly, is dependent upon the degree of neurologic impairment, and reflects ultimate outcome. The significant association with catecholamine levels suggests a role for sympathetic nervous system activation in its causation, independent of a generalized stress response, since there is no correlation of thyroid test abnormality with the degree of adrenocortical secretion.

Role of globus pallidus and substantia nigra efferent pathways in striatally evoked head turning in the rat.

These studies have examined the role of brain areas that receive efferent projections from the globus pallidus (GP) and substantia nigra (SN) in producing the contralateral head turning evoked by unilateral electrical stimulation of the neostriatum in the conscious rat. Two parameters were studied: the latency for a 90 degree head turn and changes in the normal latency evoked by administration of the GABA drugs picrotoxin and muscimol in GP. Electrolesions in the ipsilateral ventromedial and centromedian thalamic nuclei had no effect on the head turn parameters. Although small electrolesions in the SN slowed, but did not abolish the head turn, it prevented the changes in the response latency brought about by GABA drugs in GP. Treatment with 6-hydroxydopamine, which partly destroyed the nigro-striatal dopamine neurones, had no effect on the head turn. Areas of the brainstem that receive basal ganglia efferents were lesioned. An electrolesion of the nucleus tegmenti pedunculopontinus had no effect on the head turn latencies. The head turning was abolished by a lesion in the lateral periaqueductal grey (PAG); a more rostral PAG lesion, on the same level as SN, was ineffective. It is concluded that the head turning is mediated by basal ganglia efferents which pass close to the nigra without synapsing and project to the PAG. The GABA-sensitive GP efferents which modulate the response, probably project to SN.

An in vivo method for testing putative GABA-like compounds.

A technique is described that enables compounds with GABA-ergic properties to be rapidly identified in vivo. Electrical stimulation of the neostriatum in the conscious rat evoked a contralateral head-turn. Evidence is presented that this easily timed motor response involves, at least in part, GABA-ergic mechanisms in the globus pallidus. GABA drugs were injected through a cannula into the ipsilateral globus pallidus and their effects on head-turning observed. Known GABA agonists including muscimol slowed the head-turn, whereas the GABA antagonist picrotoxin facilitated it. A number of drugs such as baclofen, diazepam, and pentobarbitone which have been attributed with GABA-like properties behaved like GABA agonists in the head-turn model following either intrapallidal or intraperitoneal injection. Other drugs, e.g. tranquillizers, with no known GABA-like properties, did not effect the head-turn time.