A series of 23 Amaryllidaceae isoquinoline alkaloids and related synthetic analogues were isolated or synthesized and subsequently evaluated in cell culture against the RNA-containing flaviviruses (Japanese encephalitis, yellow fever, and dengue viruses), bunyaviruses (Punta Toro, sandfly fever, and Rift Valley fever viruses), alphavirus (Venezuelan equine encephalomyelitis virus), lentivirus (human immunodeficiency virus-type 1) and the DNA-containing vaccinia virus. Narciclasine [1], lycoricidine [2], pancratistatin [4], 7-deoxypancratistatin [5], and acetates 6-8, isonarciclasine [13a], cis-dihydronarciclasine [14a], trans-dihydronarciclasine [15a], their 7-deoxy analogues 13b-15b, lycorines 16 and 17, and pretazettine [18] exhibited consistent in vitro activity against all three flaviviruses and against the bunyaviruses, Punta Toro and Rift Valley fever virus. Activity against sandfly fever virus was only observed with 7-deoxy analogues. In most cases, however, selectivity of the active compounds was low, with toxicity in uninfected cells (TC50) occurring at concentrations within 10-fold that of the viral inhibitory concentrations (IC50). No activity was observed against human immunodeficiency virus-type 1, Venezuelan equine encephalomyelitis virus, or vaccinia viruses. Pancratistatin [4] and its 7-deoxy analogue 5 were evaluated in two murine Japanese encephalitis mouse models (differing in viral dose challenge, among other factors). In two experiments (low LD50 viral challenge, variant I), prophylactic administration of 4 at 4 and 6 mg/kg/day (2% EtOH/saline, sc, once daily for 7 days, day -1 to +5) increased survival of Japanese-encephalitis-virus-infected mice to 100% and 90%, respectively. In the same model, prophylactic administration of 5 at 40 mg/kg/day in hydroxypropylcellulose (sc, once daily for 7 days, day -1 to +5) increased survival of Japanese-encephalitis-virus-infected mice to 80%. In a second variant (high LD50 viral challenge), administration of 4 at 6 mg/kg/day (ip, twice daily for 9 days, day -1 to +7) resulted in a 50% survival rate. In all cases, there was no survival in the diluent-treated control mice. Thus, 4 and 5 demonstrated activity in mice infected with Japanese encephalitis virus but only at near toxic concentrations. To our knowledge, however, this represents a rare demonstration of chemotherapeutic efficacy (by a substance other than an interferon inducer) in a Japanese-encephalitis-virus-infected mouse model.

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Postnatal adaptation should be associated with changes in cardiac rhythmic behavior. To examine the development of heart rate variability, instantaneous heart rate (IHR) and the corresponding breathing signals of 16 healthy infants were analyzed. This was pursued by use of fast Fourier transformation beginning with the 1st day until the 6th mo of life. Power in the low-frequency range (LF, 0.02-0.2 Hz) and high-frequency range (HF, 0.2-1.5 Hz), total power (TP), the quotient LF/HF, and the frequency of the peak in LF and HF (LFF and HFF, respectively) were derived from the IHR spectrum. The peak frequency in HF (RF) was detected in the respiratory spectrum. Power and frequency of IHR rhythms undergo a marked development. TP, LF, and HF are lowest from the end of the 1st mo until the 2nd mo. LF predominates over HF, with LF/HF reaching its peak during 1- to 2-mo period. HF, recording respiratory related rhythms is negatively correlated with the breathing rate (BR). HFF and RF both show an increasing tendency during the 1st mo followed by a decrease down to the 6th mo. However, HFF is lower than RF if BR is high, mainly during the first 2 mo. The distinct changes in BR and its important influence on the IHR spectrum underscore the importance of monitoring respiration as a further measure in the diagnosis of infants. LFF is on average between 0.075 and 0.095 Hz, exhibiting an irregular course with minimum at the 10th, 21st-28th, and 90th day being apparent. The developmental pattern of LFF may by interpreted in terms of the maturation of the nervous system involved in the generation of circulatory rhythms.