Activating mutations in BRAF disrupt the hypothalamo-pituitary axis leading to hypopituitarism in mice and humans.

Germline mutations in BRAF and other components of the MAPK pathway are associated with the congenital syndromes collectively known as RASopathies. Here, we report the association of Septo-Optic Dysplasia (SOD) including hypopituitarism and Cardio-Facio-Cutaneous (CFC) syndrome in patients harbouring mutations in BRAF. Phosphoproteomic analyses demonstrate that these genetic variants are gain-of-function mutations leading to activation of the MAPK pathway. Activation of the MAPK pathway by conditional expression of the BrafV600E/+ allele, or the knock-in BrafQ241R/+ allele (corresponding to the most frequent human CFC-causing mutation, BRAF p.Q257R), leads to abnormal cell lineage determination and terminal differentiation of hormone-producing cells, causing hypopituitarism. Expression of the BrafV600E/+ allele in embryonic pituitary progenitors leads to an increased expression of cell cycle inhibitors, cell growth arrest and apoptosis, but not tumour formation. Our findings show a critical role of BRAF in hypothalamo-pituitary-axis development both in mouse and human and implicate mutations found in RASopathies as a cause of endocrine deficiencies in humans.

Early and prehospital trauma deaths: Who might benefit from advanced resuscitative care?

BACKGROUND: Recent civilian and military data from the United States and the United Kingdom suggest that further reductions in mortality will require prehospital or preoperating room hemorrhage control and blood product resuscitation. The aims of this study were to examine the potential preventability of prehospital and early in-hospital fatalities, and to consider the geographical location of such incidents, to contextualize how the use of advanced resuscitative techniques could be operationalized. METHODS: Retrospective analysis of prehospital and early in-hospital trauma deaths from January to December 2017. Data were obtained from the Coroner/ME's Office. Each death was reviewed by a panel of two trauma surgeons and a forensic pathologist. Anatomical and physiological survivabilities were evaluated separately, and then combined, leading to a holistic assessment of preventability. Incident locations were mapped and analyzed using ArcGIS. RESULTS: Three hundred sixteen trauma deaths were identified. Two hundred thirty-one (73%) were deemed anatomically not survivable; 29 (9%) anatomically survivable, but only with hospital care; 43 (14%) anatomically survivable with advanced prehospital care; and 13 (4%) anatomically survivable with basic prehospital care. Physiologically, 114 (36%) of the patients had been dead for some time when found; 137 (43%) had no cardiorespiratory effort on arrival of Emergency Medical Services (EMS) at the scene; 24 (8%) had cardiorespiratory effort at the scene, but not on arrival at the emergency department; and 41 (13%) had cardiorespiratory effort on arrival at the emergency department, but died shortly after. Combining the assessments, 10 (3%) deaths were deemed probably not preventable, 38 (12%) possibly preventable, and the remaining 278 (85%) not preventable. CONCLUSION: Twelve percent of trauma deaths were potentially preventable and might be amenable to advanced resuscitative interventions. Operationalizing this type of care will be challenging and will require either prehospital doctors, or very highly trained paramedics, nurses, or physician assistants. LEVEL OF EVIDENCE: Epidemiological, level III.

Is There a Dark Side to Mindfulness? Relation of Mindfulness to Criminogenic Cognitions.

In recent years, mindfulness-based interventions have been modified for use with inmate populations, but how this might relate to specific criminogenic cognitions has not been examined empirically. Theoretically, characteristics of mindfulness should be incompatible with distorted patterns of criminal thinking, but is this in fact the case? Among both 259 male jail inmates and 516 undergraduates, mindfulness was inversely related to the Criminogenic Cognitions Scale (CCS) through a latent variable of emotion regulation. However, in the jail sample, this mediational model also showed a direct, positive path from mindfulness to CCS, with an analogous, but nonsignificant trend in the college sample. Post hoc analyses indicate that the Nonjudgment of Self scale derived from the Mindfulness Inventory: Nine Dimensions (MI:ND) largely accounts for this apparently iatrogenic effect in both samples. Some degree of self-judgment is perhaps necessary and useful, especially among individuals involved in the criminal justice system.

Bhas 42 cell transformation activity of cigarette smoke condensate is modulated by selenium and arsenic.

Cigarette smoking remains a major health risk worldwide. Development of newer tobacco products requires the use of quantitative toxicological assays. Recently, v-Ha-ras transfected BALB/c3T3 (Bhas 42) cell transformation assay was established that simulates the two-stage animal tumorigenesis model and measures tumor initiating and promoting activities of chemicals. The present study was performed to assess the feasibility of using this Bhas 42 cell transformation assay to determine the initiation and promotion activities of cigarette smoke condensate (CSC) and its water soluble fraction. Further, the modulating effects of selenium and arsenic on cigarette smoke-induced cell transformation were investigated. Dimethyl sulfoxide (DMSO) and water extracts of CSC (CSC-D and CSC-W, respectively) were tested at concentrations of 2.5-40 µg mL(-1) in the initiation or promotion assay formats. Initiation protocol of the Bhas 42 assay showed a 3.5-fold increase in transformed foci at 40 µg mL(-1) of CSC-D but not CSC-W. The promotion phase of the assay yielded a robust dose response with CSC-D (2.5-40 µg mL(-1)) and CSC-W (20-40 µg mL(-1)). Preincubation of cells with selenium (100 nM) significantly reduced CSC-induced increase in cell transformation in initiation assay. Co-treatment of cells with a sub-toxic dose of arsenic significantly enhanced cell transformation activity of CSC-D in promotion assay. The results suggest a presence of both water soluble and insoluble tumor promoters in CSC, a role of oxidative stress in CSC-induced cell transformation, and usefulness of Bhas 42 cell transformation assay in comparing tobacco product toxicities and in studying the mechanisms of tobacco carcinogenesis.

Management of Venous Thromboembolism: Recent Advances in Oral Anticoagulation Therapy.

OBJECTIVE: To review clinical data on direct oral anticoagulants (DOACs) used in the acute treatment of venous thromboembolism (VTE) as well as practical considerations when using these products. DATA SOURCES: Searches of PubMed and Google Scholar for VTE, deep vein thrombosis, pulmonary embolism, and relevant drug international nonproprietary names were conducted. Additional online searches were conducted for prescribing information. STUDY SELECTION AND DATA EXTRACTION: Relevant articles on dabigatran, rivaroxaban, apixaban, and edoxaban for the management of VTE compared with oral vitamin K antagonists (VKAs; published between 1966 and December 2015) were reviewed and summarized, together with information on dosing, pharmacokinetics/pharmacodynamics, and drug-drug interactions. DATA SYNTHESIS: The DOACs have the potential to circumvent many of the disadvantages of VKAs. At a minimum, they greatly increase the available therapeutic options, thus providing a greater opportunity for clinicians to select a management option that best fits the needs of individual patients. Despite the significant advance that DOACs represent, they are not without risk and require careful consideration of a number of clinical issues to optimize safety and efficacy. CONCLUSIONS: The emergence of DOACs for the management of thromboembolic disorders represents a paradigm shift from oral VKAs. The DOACs provide similar efficacy and improved safety in selected patients as compared with VKAs. Clinicians treating VTE need to be familiar with the intricacies involved in using these agents, including the appropriate dose selection for the relevant indication, avoidance of drug-drug and drug-disease interactions, and consideration of dose adjustments in specific clinical situations, such as organ dysfunction.

Long-Term Pain Reduction Does Not Imply Improved Functional Outcome in Patients Treated With Combined Supraorbital and Occipital Nerve Stimulation for Chronic Migraine.

BACKGROUND: Dual supraorbital and occipital nerve stimulation (SONS and ONS) have shown promising efficacy in treating primary headaches. However, its functional outcome is not well studied. OBJECTIVE: To present functional outcome studies of combined SONS and ONS for chronic migraine using verified metrics. METHOD: Consecutive patients with both SONS and ONS assessed with Migraine Disability Assessment (MIDAS) and Beck Depression Index (BDI) both preoperatively and postoperatively were studied. Selected predictor variables included patients with ≥50% improvement of pain, disability status, number of years from diagnosis to implantation, and narcotic use. Functional outcome variables included net improvement of ranked MIDAS and BDI scores. Multivariate analysis of variance was performed to assess the correlation between the outcome and predictor variables. RESULTS: Sixteen patients (12 female; average age 52 years old) were studied. Follow-up ranged from 5 to 80 months (average 44.5; σ = 21.4 months). At most recent follow-up, eight patients had a positive response (≥50% improvement in headache), which was the only predictor of functional outcome (total MIDAS, MIDAS-B, and BDI) (p = 0.021). Of note, improvement in functional outcome was only significant during the perioperative 3-6 months period and not throughout long-term follow-up. Among the predictor variables, a strong inverse correlation was found between disability status and positive response to stimulation (r = -0.582). CONCLUSION: There is a paucity of studies in quality of life, productivity, and psychosocial aspects with peripheral nerve stimulation therapy for headache. Patients with a positive response to SONS and ONS also reported overall improvement in their functional status as reflected by MIDAS and BDI in the perioperative period. Unfortunately, this effect waned over the long-term follow-up.

Optimizing Electrical Stimulation for Promoting Satellite Cell Proliferation in Muscle Disuse Atrophy.

OBJECTIVE: The aim of this study was to investigate the optimal electrical stimulation (ES) protocol in attenuating disuse muscle atrophy by influencing satellite cell activity. DESIGN: This study used a pretest-posttest design. Six ES protocols of different duration (3 hrs day or 2 × 3 hrs day) and frequencies (2, 10, or 20 Hz) were applied on the soleus muscle in mice (n = 8 in each group) that were hindlimb-suspended for 14 days. Muscle mass, cross-sectional area and fiber-type composition, and peak tetanic force of the muscles were measured. Immunohistochemical staining was used to evaluate satellite cell content, activation, proliferation, and differentiation. Cell apoptosis was detected by TdT-mediated dUTP nick end labeling (TUNEL) assay. RESULTS: ES at 2 Hz for 2 × 3 hrs day achieved the best effect in attenuating the loss of muscle fiber cross-sectional area and force. This stimulation parameter led to a 1.2-fold increase in satellite cell proliferation and was effective in rescuing cells from apoptosis. Besides, satellite cells in the atrophic muscles required different stimulation protocols for different cellular activities such as activation, proliferation, and myogenic differentiation. CONCLUSIONS: This study showed that ES at 2 Hz for 2 × 3 hrs day is the optimal protocol for counteracting muscle disuse atrophy.

Dietary bile acid supplementation improves intestinal integrity and survival in a murine model.

PURPOSE: In vitro supplementation of the bile salt, taurodeoxycholic acid (TDCA), has been shown to stimulate proliferation and prevent intestinal apoptosis in IEC-6 cells. We hypothesize that addition of TDCA to a rodent liquid diet will be protective against induced intestinal injury. METHODS: C57Bl6 mice were fed a liquid diet with or without 50-mg/(kg d) TDCA supplementation. After 6 days, the mice were injected with lipopolysaccharide (LPS) (10 mg/kg) to induce intestinal injury. Specimens were obtained 24 hours later and evaluated for intestinal apoptosis, crypt proliferation, and villus length. A separate cohort of animals was injected with LPS (25 mg/kg) and followed 7 days for survival. RESULTS: Mice whose diet was supplemented with TDCA had significantly increased survival. After LPS-induced injury, mice supplemented with TDCA showed decreased intestinal apoptosis by both H&E and caspase-3. They also had increased intestinal proliferation by 5-bromo-2'deoxyuridine staining and increased villus length. CONCLUSIONS: Dietary TDCA supplementation alleviates mucosal damage and improves survival after LPS-induced intestinal injury. Taurodeoxycholic acid is protective of the intestinal mucosa by increasing resistance to injury-induced apoptosis, stimulating enterocyte proliferation, and increasing villus length. Taurodeoxycholic acid supplementation also results in an increased survival benefit. Therefore, bile acid supplementation may potentially protect the intestine from injury or infection.

Photoelectrochemical performance of CdSe nanorod arrays grown on a transparent conducting substrate.

Perpendicularly aligned semiconducting CdSe nanorod arrays were fabricated on ITO-coated glass substrate using porous aluminum oxide (PAO) as a hard template. Nanorod lengths were varied between 50 and 500 nm, while keeping the diameter at 65 nm. The electrochemical photovoltaic performance was found to depend critically on nanorod length and crystallinity. Arrays of rods annealed at 500 degrees C showed an order of magnitude improvement in white light power conversion efficiency over unannealed samples. The largest power conversion efficiency of 0.52% was observed for nanorods 445 +/- 82 nm in length annealed at 500 degrees C. The technique described is generally applicable to fabricating highly aligned nanorods of a broad range of materials on a robust transparent conductor.

Unfavourable expression of pharmacologic markers in mucinous colorectal cancer.

Patients with mucinous colorectal cancer generally have worse prognoses than those with the nonmucinous variety. The reason for this disparity is unclear, but may result from a differential response to adjuvant chemotherapy. We examined known molecular markers for response to common chemotherapy in these two histological subtypes. In all, 21 patients with mucinous and 30 with nonmucinous Dukes C colorectal cancer were reviewed for demographic data and outcome. Total RNA from the tumours and adjacent normal mucosa was isolated and reverse transcribed. Quantitative expression levels of drug pathway genes were determined using TaqMan RT-PCR (5-fluorouracil (5-FU): TYMS, DPYD, ECGF1; oxaliplatin: GSTP1 (glutathione S-transferase pi), ERCC1 and 2; irinotecan: ABCB1, ABCG2, CYP3A4, UGT1A1, CES2, TOP1). Mucinous tumours significantly overexpressed both TYMS and GSTP1 relative to nonmucinous tumours and patient-matched normal mucosa. No significant differences in expression of the remaining markers were found. Mean follow-up was 20 months; 17 patients had recurrent disease. Among patients receiving 5-FU, those with mucinous tumours experienced shorter disease-free survival (DFS) than those with nonmucinous tumours (median DFS 13.8 vs 46.5 months, P=0.053). Mucinous colorectal cancer overexpresses markers of resistance to 5-FU and oxaliplatin. Likewise, DFS may be decreased in patients with mucinous tumours who receive 5-FU. The presence of mucin should be carefully evaluated in developmental trials of new agents for treating colorectal cancer.

The North Dublin randomized controlled trial of structured diabetes shared care.

BACKGROUND: A new diabetes shared care service was introduced in North Dublin. It was designed as a randomized controlled trial with a complex intervention comprising education of participating practitioners, the introduction of a community-based diabetes nurse specialist, local agreement on clinical protocols and structured communication across the primary-secondary care interface. OBJECTIVES: Our aim was to assess the feasibility and effectiveness of a structured diabetes shared care service in a mixed health care system and to analyse the impact on total patient care. METHODS: A Cluster randomized controlled trial lasting 18 months was carried out in 183 patients with type 2 diabetes from 30 general practices in North Dublin. Biophysical outcomes (HbA1c, blood pressure, body mass index), psychosocial measures (smoking status and Diabetes Clinic Treatment Satisfaction and Diabetes Well-being scores) and process outcomes were collected. RESULTS: There were significant improvements in diabetes care delivery and in psychosocial outcomes, but no significant improvements in biomedical outcomes. Process data collection revealed a significant increase in diabetes care-related activity for participating patients with an increase in structured annual reviews and fewer patients defaulting from care. There were also significant improvements in information exchange between primary and secondary care. CONCLUSION: Structured diabetes shared care, in a mixed health care system, can produce significant improvements in diabetes care delivery and in psychosocial outcomes for patients, with improved information exchange across the primary-secondary care interface.

Evaluation of zinc bacitracin capsules versus placebo for enteric eradication of vancomycin-resistant Enterococcus faecium.

Patients who are colonized with enteric vancomycin-resistant Enterococcus faecium (VREF) are a major reservoir for transmission of and infection with this organism. In a randomized, controlled study to assess the effectiveness of high-dose bacitracin in the eradication of enteric VREF, 12 patients who were colonized with VREF were randomized to receive placebo (n=6) or orally administered zinc bacitracin (n=6) for 10 days. Posttreatment perirectal or stool cultures indicated that after 3 weeks, VREF had been eradicated from the stool of only 2 (33%) of 6 patients in each group. Of the 8 remaining patients who were still VREF-positive at 3 weeks after treatment, 5 (62%) had later evidence of spontaneous enteric eradication at 8 weeks. Further testing of VREF isolates revealed that a significant number (n=22, 76%) were resistant to bacitracin and that patients may have been colonized with multiple different VREF strains. Although bacitracin was not effective in the enteric eradication of VREF, the high rates of spontaneous eradication suggest that other host and environmental factors are more important in achieving long-term suppression or elimination of VREF colonization.

The North Dublin Diabetes Shared Care (DiSC) Project: a profile of current diabetes care in Ireland.

The DiSC Project aims to assess the feasibility, effectiveness and costs of diabetes shared care in Ireland. Baseline results provide a profile of diabetes care in Ireland. Thirty general practices are participating in this randomised controlled trial. Outcomes include biophysical and psychosocial measures. The majority of patients agreed to participate in diabetes shared care. Data was collected from 183 patients with type 2 diabetes. The mean age of the patients is 65 years, 56% are male and 63% are GMS eligible. The mean HBA1c was 6.8% though 21% of patients had a HBA1c>8%. The majority of patients had a blood pressure, total cholesterol and body mass index above recommended guidelines. Only half the patients are attending a dietician or a chiropodist. The majority of patients have good glycaemic control but poor blood pressure and cholesterol control. The full trial results will determine if a shared care approach can improve clinical and psychosocial outcomes for patients.

A tool to organize instructions at discharge after treatment of asthmatic children in an emergency department.

Asthma exacerbations continue to be a major cause of visits to emergency departments (ED). Comprehensive care in the outpatient setting, with planning for early intervention for exacerbations, can reduce emergency visits. Thus, a major goal of ED intervention is to establish a link between the patient and the provider of ongoing asthma care, where complete education can be achieved and reinforced over time. When designing the Asthma 1-2-3 Plan discharge teaching tool for the ED, consideration was given to educational format, readability, patient population, and setting in which education was to be delivered. To evaluate use of the plan, ED records of patients enrolled in a separate asthma study, the Neighborhood Asthma Coalition (NAC), were audited for two 8-month intervals, May-December 1993 (before initiation of the plan) and May December 1994 (starting 1 month after completion of pilot testing on the plan in the ED). To evaluate effectiveness of the plan, records of physicians who cared for children in the NAC were evaluated. The database was reviewed for the date of the first visit for planned review of asthma that occurred after the acute asthma ED visit. After introduction of the plan, the proportion of children told to return to the physician for follow-up increased from 54% to 81%. The proportion of children given advice to return to their physician within the recommended 3 days or less increased from 11% to 54%. Chi2 Analyses showed that these changes were both statistically significant (p<0.0001). The plan was not effective in achieving increased follow-up visits for regular asthma care, in that 7% returned for follow-up within 7 days after an ED visit before the plan and only 6% returned for such a visit after the Plan. Successful initiation of a focused discharge teaching tool into the routine of the ED increased appropriate advice given at time of discharge from the ED. Although unsuccessful in increasing appropriate follow-up, the present intervention uses the ED not as a base for asthma education, but as a point for contacting patients in need of regular care and education, and for promoting access to that regular care.

Antiviral (RNA) activity of selected Amaryllidaceae isoquinoline constituents and synthesis of related substances.

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.

Novel method for evaluating antiviral drugs against human cytomegalovirus in mice.

A virus-host cell system in which human cytomegalovirus-infected human cells are entrapped in agarose plugs has been developed. This model provides an inexpensive method for the in vivo evaluation (with outbred, immunocompetent mice) of antiviral drugs against human viruses such as cytomegalovirus that replicate primarily or only in human cells.

In vitro evaluation of the synergistic antiviral effects of acemannan in combination with azidothymidine and acyclovir.

The antiviral effects of selected combinations between acemannan (ACE-M), a long-chained, polydispersed, beta-(1,4)-acetylated mannan, were tested in combination with azidothymidine (AZT) and acyclovir (ACY) in vitro. The rationale for such combinations was based on the antiviral and immunomodulatory properties exhibited by ACE-M. In addition, the observed antiviral effects of ACE-M against human immunodeficiency virus type 1 (HIV-1) and other enveloped viruses appear to be related to modification of the glycosylation of viral glycoproteins. Therefore, the inhibitory effect of ACE-M does not overlap with that of AZT or ACY. The studies presented herein show that ACE-M combined with suboptimal noncytotoxic concentrations of AZT or ACY act synergistically to inhibit the replication of HIV-1 and herpes simplex virus type 1 (HSV-1), respectively. The median effect method was not applicable for analysis because the test compounds show mutually nonexclusive drug effects. For a meaningful evaluation and interpretation of the effects of drug combinations, the biological significance of combinations must be considered, that is, the protective effect of the combination, the noncytotoxicity of the combination, the mechanism(s) of action of the individual compounds comprising the combination, and so forth. With respect to effects on U1 cells latently infected with HIV-1, treatment with combinations of AZT and ACE-M does not potentiate virus replication.

Synthesis and antiviral evaluation of carbocyclic analogues of ribofuranosides of 2-amino-6-substituted-purines and of 2-amino-6-substituted-8-azapurines.

Carbocyclic analogues of ribofuranosides of 2-amino-6-substituted-purines and of 2-amino-6-substituted-8- azapurines were prepared from the 2-amino-6-chloropurine ribofuranoside analogue (2) and the 2-amino-6-chloro-8- azapurine ribofuranoside analogue (9), respectively. Analogues of purine ribofuranosides with the chloro, amino, methylamino, or methylthio group at position 6, the thioguanosine analogue, and the previously reported guanosine analogue were evaluated in vitro against herpes simplex virus, type 1 (HSV-1). 8- Azapurine ribofuranoside analogues with the chloro, amino, or methylthio group at position 6 and the previously reported 8- azaguanosine analogue were also evaluated against HSV-1. The carbocyclic analogue (6) of 2,6-diaminopurine ribofuranoside is highly active against HSV-1 and, also, against vaccinia virus. The 2-amino-6-chloropurine, 2-amino-6-(methylamino)purine, and the 2,6-diamino-8- azapurine derivatives also demonstrated significant activity against HSV-1.

Comparison of the efficacy of vidarabine, its carbocyclic analog (cyclaradine), and cyclaradine-5'-methoxyacetate in the treatment of herpes simplex virus type 1 encephalitis in mice.

The relative therapeutic effects of vidarabine (9-beta-D-arabinofuranosyladenine), cyclaradine (the adenosine deaminase-resistant carbocyclic analog of vidarabine), and cyclaradine-5'-methoxyacetate in the parenteral treatment of systemic herpes simplex virus type 1 infections in Swiss mice were determined. Among control mice inoculated intraperitoneally with virus, a mortality rate of 95% was observed. The intraperitoneal administration of nontoxic doses of vidarabine (125 to 250 mg/kg per day) or cyclaradine (113 to 450 mg/kg per day), by daily injections for 7 days beginning 4 h after virus inoculation, reduced mortality to 0 to 10%. Among control animals inoculated intracerebrally with 32 50% lethal doses of virus, 100% mortality was observed, with a mean survival time of 4.6 days. Treatment with either drug at equimolar dose levels ranging from ca. 32 to 750 mg/kg per day produced significant (P less than 0.0005), dose-dependent increases in the mean survival time of animals dying of herpesvirus encephalitis. Mice inoculated intracerebrally with 10 50% lethal doses of virus exhibited 97% mortality and a mean survival time of 5.5 to 6.4 days. Treatment with vidarabine, cyclaradine, or cyclaradine-5'-methoxyacetate significantly increased the mean survival time of dying animals and, at doses ranging from 250 to 750 mg/kg per day, produced significant increases in survival. The three drugs displayed equivalent antiviral efficacy in vivo. Drug toxicity (measured by weight loss) was not detected in mice treated with cyclaradine or cyclaradine-5'-methoxyacetate at 750 mg/kg per day, whereas severe toxicity (weight loss of greater than or equal to 3 g) was observed in mice treated with vidarabine at an equivalent dose level. Thus, cyclaradine or its 5'-methoxyacetic acid ester may possess some advantage over vidarabine in the treatment of severe herpesvirus infections and should therefore be considered for clinical trials in humans.