Defining the osteoarthritis patient: back to the future.

The history of osteoarthritis (OA) is important because it can help broaden our perspective on past and present controversies. The naming of OA, beginning with Heberden's nodes, is itself a fascinating story. According to Albert Hoffa, R. Llewellyn Jones and Archibald Edward Garrod, the name OA was introduced in the mid-nineteenth century by surgeon Richard von Volkmann who distinguished it from rheumatoid arthritis and gout. Others preferred the terms 'chronical rheumatism', 'senile arthritis', 'hypertrophic arthritis' or 'arthritis deformans'. A similar narrative applies to the concept of OA affecting the whole joint vs the 'wear-and-tear' hypothesis, inflammation and the role of the central nervous system (CNS). In the late nineteenth and early twentieth centuries, the Garrods (father and son) and Hermann Senator argued that OA was a whole joint disease, and that inflammation played a major role in its progression. Garrod Jnr and John Spender also linked OA to a neurogenic lesion 'outside the joint'. The remaining twentieth century was no less dynamic, with major advances in basic science, diagnostics, treatments, surgical interventions and technologies. Today, OA is characterized as a multi-disease with inflammation, immune and CNS dysfunction playing central roles in whole joint damage, injury progression, pain and disability. In the current 'omics' era (genomics, proteomics and metabolomics), we owe a great debt to past physicians and surgeons who dared to think 'outside-the-box' to explain and treat OA. Over 130 years later, despite these developments, we still don't fully understand the underlying complexities of OA, and we still don't have a cure.

Rapid regression of pituitary prolactinomas during bromocriptine treatment.

Therapy for large prolactinomas remains controversial. Surgery is often unsuccessful in restoring endocrine function to normal. However, medical therapy with bromocriptine, a dopamine agonist, not only suppresses PRL levels, but may also lead to a reduction in tumor size. Previous reports have demonstrated radiographic evidence of tumor regression only after 3 or more months of bromocriptine therapy. We have now documented, for the first time, objective evidence of extremely rapid reduction in tumor size in two patients harboring large PRL-secreting pituitary tumors (mean pretreatment serum PRL levels, 2350 and 3900 ng/ml) who were prospectively treated with bromocriptine (7.5 mg/day) in preference to surgical intervention despite marked visual impairment in one of the patients. After 2 and 6 weeks of therapy, respectively, marked reduction in tumor size was demonstrated radiographically in both patients. Headache, visual acuity, and visual fields had improved after only 3 days. Although the mechanism of bromocriptine's antitumor activity is unclear, we believe that a large prospective trial to study the effects of bromocriptine therapy on the size of PRL-secreting macroadenomas is urgently needed to determine whether medical therapy should become the primary modality of treatment to reduce tumor size as well as restore endocrine function.

Neurochemical differentiation of functionally distinct populations of autonomic neurons.

The coeliac ganglion of guinea pigs displays a unique topographical arrangement of neurochemically and functionally distinct populations of sympathetic neurons. The authors used multiple-labeling immunohistochemistry to investigate the neurochemical differentiation of these neurons during embryonic and fetal development. Sympathoadrenal precursors, located on either side of the abdominal aorta, were intensely immunoreactive for tyrosine hydroxylase (TH-IR), neurofilament, and the human natural killer 1 antibody at midembryonic stages (Carnegie stages 16-19). During late embryonic stages (stages 20-23), a single bilobed ganglion had formed. At this time, neuropeptide Y immunoreactivity (NPY-IR) was widely expressed in sympathetic neurons (with moderate TH-IR) and chromaffin cells (with intense TH-IR). The onset of somatostatin (Som-IR) expression followed that of NPY-IR and was restricted to sympathetic neurons. However, at late embryonic stages, most TH-IR neurons with Som-IR also expressed NPY-IR (a combination of peptides not found in the mature coeliac ganglion). Between late embryonic stages and the end of the early fetal period, there was a significant increase in the proportion of neurons in lateral regions that had both NPY-IR and TH-IR. At the same time, there was an increase in the proportion of neurons in medial regions that had both Som-IR and TH-IR. Neurons expressing both Som-IR and TH-IR were rarely observed in lateral regions of the coeliac ganglion. Thus, a clear topography within the coeliac ganglion is established during late embryonic and early fetal stages of development and reflects that found in the mature animal by the end of the early fetal period.

Neuropeptide Y immunoreactivity in cutaneous sympathetic and sensory neurons during development of the guinea pig.

Different levels of the cutaneous vasculature are innervated selectively by subpopulations of sympathetic neurons distinguished by the presence or absence of immunoreactivity (-IR) for neuropeptide Y (NPY). This study used multiple-labelling immunohistochemistry to examine the appearance of NPY-IR in neurons innervating cutaneous vessels in the ear pinna of embryonic, fetal, and neonatal guinea pigs. NPY-immunoreactive axons were detected in the ear bud at embryonic day 25. However, these axons lacked IR for tyrosine hydroxylase (TH) and often ran in bundles with substance P (SP)-immunoreactive axons close to the epidermis. Many neuronal somata in the cervical dorsal root ganglia (DRG) at late embryonic stages contained NPY-IR with or without SP-IR, but no NPY-IR was detected in DRG or subepidermal axons by late fetal stages. IR for calcitonin gene-related peptide increased in DRG neurons from midfetal to late fetal stages, after the decrease in NPY-IR. Populations of TH-IR neurons with or without NPY-IR were present in the superior cervical ganglion (SCG) from midembryonic stages. TH-immunoreactive axons were not detected in the ear pinna until midfetal stages, when axons with TH-IR and NPY-IR innervated proximal arteries and TH-immunoreactive axons without NPY-IR innervated distal vessels. Vasoactive intestinal peptide-IR was detected transiently in most fetal SCG neurons with TH-IR and NPY-IR but was not detected in cutaneous axons. These results demonstrate that selective expression of NPY by subpopulations of sympathetic neurons occurs prior to innervation of their targets. This suggests that target contact is not required to establish appropriate patterns of expression of peptide neurotransmitters by cutaneous sympathetic neurons.

Subpopulations of sympathetic neurons project to specific vascular targets in the pinna of the rabbit ear.

We have characterised sympathetic neurons projecting to a range of cutaneous and striated muscle vascular targets in the pinna of the rabbit ear by examining neurotransmitter-related enzymes and peptides in perivascular axons and in somata identified by retrograde axonal tracing. Fast Blue was injected into one of seven sites in each pinna (n = 21 pinnae). The soma cross-sectional area and immunoreactivity (IR) for tyrosine hydroxylase (TH) and neuropeptide Y (NPY) were determined for each of 2,041 retrogradely labelled neurons in the ipsilateral superior cervical ganglion (SCG) or stellate ganglion (StG). Larger neurons in the SCG with TH-IR but not NPY-IR projected predominantly to veins along the medial edge of the pinna. Larger neurons in the StG with TH-IR but not NPY-IR projected predominantly to arteries and veins in the tip and lateral edge of the pinna. Smaller neurons in the SCG with IR to both TH and NPY projected predominantly to arteries in the striated muscles at the base of the ear. The smallest retrogradely labelled neurons in the SCG or StG lacked TH-IR but contained NPY-IR and projected almost exclusively to arterial vessels in the lateral muscle at the base of the ear. Thus, somata of sympathetic neurons projecting to cutaneous versus striated muscle vessels or to different regions of the cutaneous bed could be distinguished by a combination of location, size, and immunohistochemical profile. Consequently, regulation of blood flow within the rabbit ear is likely to involve coordination between neuronal pathways containing neurochemically and morphologically distinct populations of sympathetic neurons.

Levodopa improves spatial contrast sensitivity in Parkinson's disease.

OBJECTIVE: To study the effect of levodopa on the visual contrast sensitivity of patients with Parkinson's disease. DESIGN: Contrast sensitivity of patients was measured before and after levodopa administration. Patient contrast sensitivity was compared with that of normal controls by repeated-measures analyses of variance. SETTING: Parkinson's disease research center associated with private neurology practice. PATIENTS: Fifteen patients with idiopathic Parkinson's disease (eight men, seven women; mean age, 71.8 years) and 22 normal controls (10 men, 12 women; mean age, 68.0 years) volunteered for the study. INTERVENTION: Levodopa/carbidopa (Sinemet). MAIN OUTCOME MEASURE: Change in contrast sensitivity of parkinsonian patients. RESULTS: Following levodopa treatment, the contrast sensitivity of parkinsonian patients improved significantly at the three lowest spatial frequencies tested (0.4, 1, and 2 cycles per degree). CONCLUSIONS: Levodopa improves low-frequency contrast sensitivity in parkinsonian patients. Initially deficient contrast sensitivity in such patients may be restored to near normal levels by levodopa therapy.

Treatment of chronic Parkinson's disease with controlled-release carbidopa/levodopa.

Controlled-release carbidopa/levodopa 50/200 (SINEMET CR) and standard carbidopa/levodopa (SINEMET 25/100) were compared in a double-blind, six-month, crossover study involving 21 patients with chronic Parkinson's disease and motor response fluctuations. Daily dosage frequency was significantly reduced with SINEMET CR compared with SINEMET 25/100, while the daily amount of levodopa required with SINEMET CR was significantly greater. No significant differences in disability ratings, motor response fluctuations, or safety were detected during double-blind conditions. In the open-label, dose-finding phase of the study, SINEMET CR was superior to standard SINEMET 25/100 in patient ratings of percent "on" time (good motor function), clinical assessments of motor function, and activities of daily living. This finding resulted from a depreciation of the value of the "old drug" rather than an overestimation of the value of the experimental drug. This double-blind study also suggested that elderly male patients with Parkinson's disease derived the greatest benefit from SINEMET CR.

Long-acting carbidopa-levodopa in the management of moderate and advanced Parkinson's disease.

Parkinson's disease patients treated chronically with levodopa often develop fluctuations in motor response. Motor fluctuations can be attributed in part to oscillating plasma levodopa concentrations. A controlled-release formulation containing 200 mg of levodopa and 50 mg of carbidopa provides superior plasma levodopa profiles compared with the standard preparation. A multicenter, double-blind trial involving 202 patients with fluctuating motor response found controlled-release carbidopa-levodopa to be safe and tolerable, with improved efficacy compared with the standard formulation. Long-term exposure to the controlled-release formulation, at least for a period of 3 years, does not appear to be associated with any increase in the incidence of adverse side effects.

Controlled study of the antiparkinsonian activity and tolerability of cabergoline.

Cabergoline, a new ergoline derivative, is a D2-specific dopaminergic agonist that is more potent and longer-acting than other agonist agents. We conducted a randomized, double-blind study of increasing doses of cabergoline taken once a day. Twenty-five patients with Parkinson's disease taking stable doses of levodopa began cabergoline at 0.5 mg. The dose was escalated at weekly intervals to 1.0 mg in 19 patients, 1.5 mg in 14 patients, 2.0 mg in nine patients, and 2.5 mg in four patients. Treatment continued for 8 weeks after titration. Unified Parkinson's Disease Rating Scale scores, Hoehn and Yahr stage of disease, and computerized measures of motor performance improved significantly with cabergoline treatment. Dose-response effects were not significant. No serious adverse experiences occurred during the 13-week trial, and the side-effect profile mirrored other dopaminergic agonists. Cabergoline appears to be a promising agent in the treatment of Parkinson's disease.

Spatial contrast sensitivity is reduced in bilateral Parkinson's disease.

We studied the contrast sensitivity functions of 41 patients with idiopathic Parkinson's disease (PD) with a wide range of parkinsonian symptomatology (Hoehn and Yahr stages 1 to 4) and 22 age-matched control subjects in a parametric design. Results demonstrated reduced contrast sensitivity in PD patients but only in those patients who had progressed beyond Hoehn and Yahr stage 1. Furthermore, there were deficits in contrast sensitivity related to the severity of PD.

Contrast sensitivity dysfunction in Alzheimer's disease.

We compared the spatial contrast sensitivity of six patients with mild to moderate Alzheimer's disease (AD) and six age-matched control subjects in a parametric design. Results demonstrate reduced contrast sensitivity in patients with AD at all but the lowest frequency tested. The results suggest that the effect of AD on spatial contrast sensitivity is stronger at higher frequencies and provide a rationale for complaints of poor vision in AD patients.

Multicenter controlled study of Sinemet CR vs Sinemet (25/100) in advanced Parkinson's disease.

Controlled-release carbidopa/levodopa 50/200 (Sinemet CR) and standard carbidopa/levodopa (Sinemet 25/100) were compared in a multicenter double-blind trial involving 202 patients with advanced Parkinson's disease and motor response fluctuations. Treatment with Sinemet CR significantly reduced daily "off" time. According to both physician and patient global ratings, patients showed significant improvements with Sinemet CR compared to treatment with standard Sinemet. Patients preferred Sinemet CR treatment by a ratio of approximately 2 to 1. Daily dosing frequency was 33% less with Sinemet CR, while daily intake of levodopa required was increased by 25%. The safety profiles of the 2 formulations were similar. We conclude that Sinemet CR is superior to standard Sinemet for many patients with advanced Parkinson's disease, although it does not solve the problem of fluctuating motor performance.

Multicenter, placebo-controlled trial of cabergoline taken once daily in the treatment of Parkinson's disease.

Cabergoline is a dopaminergic agonist relatively specific for the D2 receptor and much longer-acting than other dopamine agonists. We conducted a randomized, placebo-controlled, double-blind study of cabergoline in 188 levodopa/carbidopa-treated patients with suboptimally controlled Parkinson's disease (PD). The cabergoline patients had significantly better Activities of Daily Living (p = 0.032) and Motor Examination (p = 0.031) scores at the conclusion of the trial compared with the placebo group. The daily levodopa dose for the cabergoline patients decreased 18% compared with a 3% reduction for the placebo group (p < 0.001). The amount of time in the "on" state increased more in the cabergoline group (p = 0.022). The side-effect was similar to that seen with other dopamine agonists, and cabergoline was generally well tolerated. We conclude that cabergoline is an effective adjunct to levodopa for the treatment of PD.

Ventricular dilation after anterior ST-elevation myocardial infarction in the thrombolytic era.

BACKGROUND: The aim of this work was to study changes in end-diastolic volume 6 months after Q-wave and non-Q-wave anterior ST-elevation myocardial infarction by echocardiography. Ventricular dilation after anterior Q-wave myocardial infarction is well-recognized. However, there is a dearth of information about the natural history of ventricular volumes after non-Q-wave myocardial infarction. METHODS: One hundred ninety patients receiving thrombolytic therapy after anterior ST-elevation myocardial infarction were studied. All patients had 2D echocardiograms and 12-lead electrocardiograms recorded within 24 hours of symptoms and at 3, 42, and 180 days later. In addition, a further electrocardiogram was recorded on day 7 to assess patients for the presence of Q waves. Peak creatine kinase over the first 3 days of admission was recorded. End-diastolic volume index was the study end point. RESULTS: Peak creatine kinase was strongly associated with ventricular dilation in both groups (P <.001). Mean end-diastolic volume in the Q-wave group increased significantly from day 1 to 6 months (P <.05) but did not alter after non-Q-wave infarction. However, when patients were selected on predefined criteria for significant change in ventricular dilation (>10 mL/m(2)), then 35% of those with and 15% of those without Q waves fell into this category. Within this group, the increase in end-diastolic volume followed a similar pattern, with the maximum percentage increase occurring between day 1 and 6 weeks. CONCLUSIONS: In the postthrombolytic group of anterior ST-elevation myocardial infarction, a minority of patients without Q-wave development also undergo significant ventricular dilation.

Multiple populations of neuropeptide-containing intrinsic neurons in the guinea-pig heart.

Recent studies of autonomic ganglia have shown that specific combinations of neuropeptides and other potential neurotransmitters distinguish different functional types of neurons. In the present paper the patterns of coexistence of neurochemicals in guinea-pig cardiac ganglion cells was examined, using multiple-labelling immunohistochemistry. Many neurons were found to contain somatostatin immunoreactivity with various combinations of immunoreactivity for dynorphin B, substance P, neuropeptide Y and nitric oxide synthase. There were several small populations of neurons without somatostatin immunoreactivity, which contained combinations of immunoreactivity for vasoactive intestinal peptide, neuropeptide Y, dynorphin B, substance P and nitric oxide synthase. Possible synaptic inputs to these populations of ganglion cells were identified using multiple-labelling immunohistochemistry combined with long-term organ culture. These experiments demonstrated that cardiac ganglia contain prominent pericellular baskets of varicose nerve terminals of sympathetic and sensory origin. In addition, populations of intrinsic intraganglionic nerve terminals were identified which were immunoreactive for vasoactive intestinal peptide, neuropeptide Y or both peptides. These terminals presumably originate from intrinsic neurons, with the same combinations of neuropeptides, located in other cardiac ganglia. These results have demonstrated that there are diverse populations of cardiac ganglion cells in the guinea-pig and that some of these neurons may act as interneurons within the intrinsic cardiac plexuses. Therefore it is highly likely that vagal transmission in the heart is modified by sympathetic, sensory and intrinsic neurons and that cardiac ganglia are complex integrators of convergent neuronal activity rather than simple relays.

Differential expression of calcium channels in sympathetic and parasympathetic preganglionic inputs to neurons in paracervical ganglia of guinea-pigs.

Neurons in pelvic ganglia receive nicotinic excitatory post-synaptic potentials (EPSPs) from sacral preganglionic neurons via the pelvic nerve, lumbar preganglionic neurons via the hypogastric nerve or both. We tested the effect of a range of calcium channel antagonists on EPSPs evoked in paracervical ganglia of female guinea-pigs after pelvic or hypogastric nerve stimulation. omega-Conotoxin GVIA (CTX GVIA, 100 nM) or the novel N-type calcium channel antagonist, CTX CVID (100 nM) reduced the amplitude of EPSPs evoked after pelvic nerve stimulation by 50-75% but had no effect on EPSPs evoked by hypogastric nerve stimulation. Combined addition of CTX GVIA and CTX CVID was no more effective than either antagonist alone. EPSPs evoked by stimulating either nerve trunk were not inhibited by the P/Q calcium channel antagonist, omega-agatoxin IVA (100 nM), nor the L-type calcium channel antagonist, nifedipine (30 microM). SNX 482 (300 nM), an antagonist at some R-type calcium channels, inhibited EPSPs after hypogastric nerve stimulation by 20% but had little effect on EPSPs after pelvic nerve stimulation. Amiloride (100 microM) inhibited EPSPs after stimulation of either trunk by 40%, while nickel (100 microM) was ineffective. CTX GVIA or CTX CVID (100 nM) also slowed the rate of action potential repolarization and reduced afterhyperpolarization amplitude in paracervical neurons. Thus, release of transmitter from the terminals of sacral preganglionic neurons is largely dependent on calcium influx through N-type calcium channels, although an unknown calcium channel which is resistant to selective antagonists also contributes to release. Release of transmitter from lumbar preganglionic neurons does not require calcium entry through either conventional N-type calcium channels or the variant CTX CVID-sensitive N-type calcium channel and seems to be mediated largely by a novel calcium channel.

Somatostatin is contained in and released from cholinergic nerves in the heart of the toad Bufo marinus.

The heart of the toad Bufo marinus contained a substance with somatostatin-like immunoreactivity which eluted with somatostatin on reverse phase high pressure liquid chromatography. Immunoreactivity to somatostatin was localised histochemically to nerve fibers in muscle bundles of the sinus venosus, atria and ventricles and to nerve cell bodies in the sinus venosus and inter-atrial septum. Nerve cell bodies were localised both by interference contrast microscopy and immunohistochemistry; all detectable intracardiac neurons were immunoreactive. Synthetic somatostatin inhibited the rate and force of beat of atrial preparations, but did not affect the driven ventricle. Vagal stimulation caused inhibition of all cardiac chambers. After muscarinic blockade with hyoscine, vagal stimulation with 3 Hz or more still caused inhibition of the pacemaker and atrium, but not of the ventricle. The hyoscine-resistant vagal effects were diminished by about 60% after induction of tachyphylaxis to somatostatin. When when the vagus nerves were stimulated intermittently for 1 h at 10 Hz, in the presence or absence of hyoscine, the effect of somatostatin was reduced by about 60%. It is concluded that the cholinergic postganglionic neurons of the cardiac vagus contain somatostatin. When the vagus is stimulated at 3 Hz or more, the neurons release sufficient somatostatin to inhibit the pacemaker and atrial muscle.

Blockade of noradrenaline-induced constrictions by yohimbine and prazosin differs between consecutive segments of cutaneous arteries in guinea-pig ears.

1. The study has examined the receptors mediating constriction produced by brief local application of noradrenaline (NA) to cutaneous arteries and arterioles in the ear vasculature of anaesthetized guinea-pigs. The innervation of the corresponding vascular segments has been examined immunohistochemically at the conclusion of the pharmacological experiments. 2. Small arteries of branch order 4 (4 degrees, 40-110 microns internal diameter) were more sensitive to the vasoconstrictor action of NA than were more proximal arteries of branch order 3 (3 degrees, 60-150 microns internal diameter), or more distal arteries and arterioles of branch orders 5 to 7 (5 degrees-7 degrees, 18-85 microns internal diameter). This higher sensitivity of 4 degrees arteries was maintained after blockade of neuronal uptake with desipramine (1 microM), and after blockade of beta-adrenoceptors with propranolol (1 microM). 3. NA-induced vasoconstrictions of distal arterioles (5 degrees-7 degrees) were abolished or greatly reduced by yohimbine (1 microM). The blockade by yohimbine decreased progressively with increasing vessel diameter of proximal arteries, while the blockade by prazosin (1 microM) increased progressively in arteries > 40 microns diameter. 4. In 3 degrees and 4 degrees arteries, a substantial component (approximately 50%) of NA-induced vasoconstrictions remained after combined treatment with yohimbine and prazosin, in the presence or absence of desipramine. These constrictions were not further reduced by benextramine (1-10 microM), but were abolished by dihydroergotamine (1-10 microM). Constrictions induced by ATP (0.1-1 mM) were not affected by dihydroergotamine. 5. 5-Hydroxytryptamine (3-100 microM) had a variable effect on 3 degree and 4 degree arteries including: concentration dependent constrictions (n = 3); small constrictions at some concentrations, and dilatations or no change in diameter at other concentrations (n = 6); concentration-dependent dilatations only (n = 3). The 5-HT2 receptor antagonist, ketanserin (0.1-0.3 micro M), did not affect NA-induced constrictions.6. In 16 arterial segments ranging from 3 degree arteries to 60 arterioles, there was a significant correlation between the presence of neuropeptide Y-immunoreactive (NPY-IR) sympathetic axons and the degree of blockade of NA-induced constrictions by yohimbine, prazosin and dihydroergotamine.7. These results demonstrate marked differences in the postsynaptic adrenoceptors mediating vasoconstriction to a bolus of NA applied briefly to the adventitial surface of different segments of the cutaneous vasculature of the guinea-pig ear. Furthermore, the presence or absence of adrenoceptors sensitive to blockade by yohimbine or prazosin is related to the proportion of sympathetic axons innervating each vascular segment which contain NPY-IR.

Selective inhibition of arthropod-borne and arenaviruses in vitro by 3'-fluoro-3'-deoxyadenosine.

A novel nucleoside analog, 3'-fluoro-3'-deoxyadenosine (3'F3'dAdo), was evaluated for antiviral activity against several arthropod-borne and arenaviruses in Vero cell culture. The following 50% inhibitory concentrations (EC50) of virus plaque formation were obtained against the test viruses: Semliki Forest (10.3 microM) and Venezuelan equine encephalitis (5.3 microM) alphaviruses, lymphocytic choriomeningitis (7.7 microM) and Pichinde (greater than 32 microM) arenaviruses, Punta Toro (greater than 32 microM) and San Angelo (1.6 microM) bunyaviruses, banzi flavivirus (4.0 microM), and Colorado tick fever orbivirus (0.6 microM). By comparison, the broad-spectrum antiviral agent ribavirin was active against lymphocytic choriomeningitis (18 microM), Pichinde (24 microM), Punta Toro (114 microM), and San Angelo (99 microM) viruses, but was less active against the other 4 viruses (greater than 200 microM). Vero cell proliferation and thymidine and uridine incorporation into replicating Vero cells were inhibited by 50% with 3'F3'dAdo concentrations of 36, 45, and 32 microM, respectively. In virus yield reduction assays, increasing the multiplicity of infections of Semliki Forest and Venezuelan equine encephalitis viruses reduced the inhibitory activity of 3'F3'dAdo. Using the same assay, 3'F3'dAdo was found to enhance Punta Toro virus replication up to 5-fold relative to the untreated control. By adding the nucleoside transport inhibitor nitrobenzylthioinosine (100 microM) to the culture medium, antiviral activity against the two alphaviruses was eliminated, indicating that 3'F3'dAdo uses the nucleoside transport system for cell entry. When actinomycin D (5 microM) was used to greatly suppress cellular RNA synthesis in Semliki Forest virus-infected and uninfected cells, 3'F3'dAdo preferentially inhibited viral RNA synthesis. The results of these studies indicate 3'F3'dAdo is a selective inhibitor of most of the viruses tested and should be a promising candidate for in vivo evaluations.

Evaluation of the antiviral activity of anthraquinones, anthrones and anthraquinone derivatives against human cytomegalovirus.

A number of anthraquinones, anthrones and anthraquinone derivatives were evaluated for antiviral activity against human cytomegalovirus (HCMV) as well as for cytotoxicity. Of those compounds evaluated, quinalizarin, emodin, rhein, hypericin, protohypericin, alizarin, emodin bianthrone and emodin anthrone showed antiviral activity against a normal laboratory HCMV strain, AD-169. When tested against a ganciclovir-resistant strain of HCMV, the EC50 values for quinalizarin, rhein and alizarin were superior to the values obtained for the AD-169 strain of HCMV. These results suggest that these compounds will be useful as prototypes for synthesizing a class of anti-HCMV drugs that are effective against ganciclovir-sensitive and -resistant strains of HCMV.