The role of clinical pharmacology in supporting the emergency use authorization of an unapproved anti-influenza drug, peramivir.

On 23 October 2009, the commissioner of the US Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for peramivir for intravenous injection, an unapproved neuraminidase inhibitor used for treating certain hospitalized adult and pediatric patients infected with 2009 H1N1 influenza. This was the first EUA of an unapproved drug product. This report summarizes the critical contributions of the clinical pharmacology review team in support of the peramivir EUA.

Effects of Cyanide Ion and Hypoxia on the Volumes of Second-Stage Juveniles of Meloidogyne incognita in Polyethylene Glycol Solutions.

Changes in the volumes of second-stage juveniles of Meloidogyne incognita were monitored in aqueous solutions of polyethylene glycol supplemented with dilute balanced salts. At key points within a 48-hour cycle of fluctuating water potential, nematodes were placed under hypoxic conditions or exposed to the respiratory inhibitor, sodium cyanide, to detect any respiration-dependent process that regulates volume. Aerobic respiratory arrest at -500 kPa induced pronounced water loss, lateral and dorsoventral collapse of the body wall, and abnormal failure to shorten longitudinally. Durations of hypoxia that were innocuous in dilute solutions were lethal during 500 kPa increases and decreases in water potential; the same water potential changes under aerobic conditions had no effect on viability. Data are consistent with the hypothesis that respiration is essential to survive water potential changes.

Influence of Soil Temperature on Meloidogyne incognita Resistant and Susceptible Cotton, Gossypium hirsutum.

The degree of resistance by a cotton plant to Meloidogyne incognita is affected by soil temperature, particularly in moderately resistant cultivars, The total number of nematodes in the resistant and moderately resistant rools at 35 C was equal to, or greater than, the number in susceptible roots at 20, 25, or 30 C. A shift in numbers to developing and egg-bearing forms of nematodes in the susceptible cultivar as tentperature increased indicates development was affected by temperature rather than by genetic resistance mechanisms. However, the nematode resistant cultivar did not support maturation of nematodes until a soil tempurature of 35 C was attained. This indicated that resistance mechanisms are partially repressed at 35 C and differences in nematode development cannot be explained in terms of accumulated heat units. The moderately resistant cultivar was significantly more sensitive to the effects of high temperature than was the resistant cultivar.

A modification of imazalil residue analysis in treated grapefruit.

Residues of imazalil, 1-[2-(2,4-dichlorophenyl)-2-(2-propenyloxy)ethyl]-1H-imidazole, a fungicide that prevents decay of citrus, were determined in treated grapefruit. The method consists of a simplified heptance-isoamyl extraction solvent, acid-base clean-up, and direct gas chromatographic analysis with electron-capture detection.

Resistance and Resistant Reaction of Gossypium arboreum to the Reniform, Nematode, Rotylenchulus reniformis.

Gossypium arboreum 'Nanking CB 1402' possessed a high level of resistance to Rotylenchulus reniformis. Within 16 h, the nematode penetrated roots of resistant and susceptible cottons equally. After 36 h, significantly fewer nematodes were found in resistant roots. Larvae fed in either an endodermal or pericyclic cell and had no specificity for root tissue of a particular age. In roots of resistant G. arboreum '1402,' wall breakdown of pericyclic cells was evident after 3 d, endodermal and cortical cells collapsed, and the hypertrophied pericyclic cells disintegrated within 12 d. Cell walls immediately adjacent to the nematode's head were thickened and more safranin positive in resistant than in susceptible cotton cultivars. Several other cultivars of G. arboreum were also resistant to R. reniformis, based on nematode fecundity and percent egg reduction.

Effects of soil temperatures and inoculum levels of Meloidogyne incognita and Rhizoctonia solani on seedling disease of cotton.

Soreshin of cotton was more severe from combined infections of Rhizoctonia solani and Meloidogyne incognita than from either organism alone, when both critical soil temperature and inoculum concentrations were present. Optimum soil temperatures for disease development from combined infections were 18 and 21 C. Either 2,500 or 5,000 M. incognita larvae per plant, combined with R. solani, increased seedling disease severity over that caused by R. solani alone. When 100 or 500 larvae per plant were added with R. solani, disease severity did not change. Disease severity increased with the highest level of R. solani inoculum either alone or combined with M. incognita.

Effects of soil texture on the interaction between Rhizoctonia solani and Meloidogyne incognita on cotton seedlings.

Soils containing 60, 75, and 90% coarse particles (sand plus coarse silt) were prepared by dilution of a field soil with 246microm (60-mesh) silica sand. As the coarse-particle content of the soils increased, the synergistic interaction between Meloidogyne incognita and Rhizoctonia solani on cotton seedlings increased. Increasing the coarse-particle content of the soil also increased damage from the nematode alone and slightly increased soreshin damage from R. solani alone.

Symptomless Resistance of Alfalfa to Meloidogyne incognita acrita.

Penetration, development and migration of the cotton root-knot nematode, Meloidogyne incognita acrita, in resistant and susceptible alfalfa varieties was compared. Larvae entered both resistant and susceptible plants in approximately the same numbers. After 3 to 4 days, the number of larvae in resistant roots decreased sharply until at 7 days fewer than 5 larvae/seedling and no nematode development could be found. In susceptible roots, larvae became sedentary and developed normally; egg production began as early as 18 days after penetration of the host.