Detecting high blood pressure in an industrial population. Report on a hypertension screening program at Merck & Co., Inc.
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Comparison of two strategies for intensifying antihypertensive treatment: low-dose combination (enalapril + felodipine ER) versus increased dose of monotherapy (enalapril). LEVEL (Lexxel vs Enalapril) Study Group.
To compare two popular strategies for intensifying treatment for hypertension, a double-blind, randomized, prospective, parallel-group, and partial crossover study was done. After 2 weeks of placebo run-in (baseline) and 3 weeks of 5 mg enalapril once daily, 217 patients were randomized to 6 weeks of treatment with either a low-dose combination therapy (5 mg enalapril + 5 mg felodipine ER once daily, Lexxel, Astra Merck, Inc.), or a higher dose of monotherapy (10 mg enalapril once daily, Vasotec, Merck & Co., Inc.). The group randomized to the combination had significantly greater reductions in sitting systolic/diastolic blood pressure (BP)--14.2/10.6 mm Hg compared with baseline versus 9.6/7.4 mm Hg (P < .05/.01)--as well as a greater percentage of patients having achieved either diastolic BP < 90 mm Hg or a decline of at least 10 mm Hg (responders), 59% v 41% (P < .01). When patients originally taking 10 mg enalapril were crossed over to the combination therapy for a further 6 weeks, there was a further BP reduction and increase in response rate, with loss of significant differences compared with those treated continuously with the combination for the entire 12 weeks. The greater BP-lowering efficacy of the combination was independent of age, gender, and race. There were no significant differences in tolerability between the regimens. These data support the hypothesis that in patients who do not achieve goal BP reduction with a low dose of an antihypertensive agent, a combination of two drugs with complementary mechanisms of action is more effective than increasing the dose of the first agent.
Aged↗
Effects of the anthelmintics clorsulon, rafoxanide, mebendazole and arprinocid on Echinostoma caproni in ICR mice [corrected and reapublished in J Helminthol 1996 Mar;70(1):95-6].
Female ICR mice, 5 to 6 weeks old, were exposed by stomach tube to 25 metacercarial cysts of Echinostoma caproni per mouse. At 14 days post-exposure, mice were fed by stomach tube clorsulon (1000 mg/kg, 500 mg/kg and 100 mg/kg) or rafoxanide (50 mg/kg, 25 mg/kg and 5 mg/kg) dissolved in dimethylsulphoxide (DMSO) carrier and mebendazole (1000 mg/kg and 500 mg/kg) or arprinocid (100 mg/kg and 50 mg/kg) suspended in a 2:1 polyethylene glycol (PEG)/DMSO carrier. All drugs were obtained from Merck Inc. (Rahway, New Jersey, USA) and only single dose regimes were used. Experimentally infected mice that served as controls received either DMSO or 2:1 PEG/DMSO carriers or were not given the carrier. Mice were necropsied 15v, 16, 18 and 20 days postexposure to worms. Doses of 100 mg/kg of clorsulon and 50 mg/kg of rafoxanide were 100% effective in eliminating the echinostomes on day 1 post-administration of the anthelmintics. Mebendazole and arprinocid were ineffective in eliminating worms at 1 or 2 days post drug administration.
Adenine↗
Effects of the anthelmintics clorsulon, rafoxanide, mebendazole and arprinocid on Echinostoma caproni in ICR mice.
Female ICR mice, 5 to 6 weeks old, were exposed by stomach tube to 25 metacercarial cysts of Echinostoma caproni per mouse. At 14 days post-exposure, mice were fed by stomach tube clorsulon (1000 mg/kg, 500 mg/kg and 100 mg/ kg) or rafoxanide (50 mg/kg, 25 mg/kg and 5 mg/kg) dissolved in dimethylsulphoxide (DMSO) carrier and mebendazole (1000 mg/kg and 500 mg/ kg) or arprinocid (100 mg/kg and 50 mg/kg) suspended in a 2:1 polyethylene glycol (PEG)/DMSO carrier. All drugs were obtained from Merck Inc. (Rahway, New Jersey, USA) and only single dose regimes were used. Experimentally infected mice that served as controls received either DMSO or 2:1 PEG/DMSO carriers or were not given the carrier. Mice were necropsied 15, 16, 18 and 20 days postexposure to worms. Doses of 100 mg/kg of clorsulon and 50 mg/kg of rafoxanide were 100% effective in eliminating the echinostomes on day 1 post-administration of the anthelmintics. Mebendazole and arprinocid were ineffective in eliminating worms at 1 or 2 days post drug administration.
Adenine↗
Systemic beta-blockade with once daily Betimol or Timoptic-XE.
The purpose of this study was to evaluate the effect of timolol hemihydrate 0.5% (Betimol [THH], Ciba Vision Ophthalmics) and timolol maleate gel forming solution 0.5% (Timoptic-XE , [TXE], Merck, Inc.), when both are dosed once daily on the exercise performance. Maximum exercise heart rate reflects systemic beta-blockade activity. Fourteen healthy subjects were randomized to receive either placebo (HypoTears , Ciba Vision Ophthalmics), THH, or TXE by a Latin square technique in a three period crossover design. Subjects were dosed one drop every morning beginning three days before exercise testing. The interval between each test was one week. Exercise testing was performed two hours after dosing. Maximum exercise heart rate showed no statistical difference between TXE and THH (174 +/- 13.1 vs. 172 +/- 14.9 beats/min, respectively, P = 0.72). Both active treatments, however, decreased heart rate compared to placebo (185 +/- 7.3 beats/min, P = 0.017). Time to exhaustion showed no difference between groups (P > 0.10). The double product (product of heart rate and systolic blood pressure) did not show a difference between TXE and THH (P = 0.38) but was reduced compared to placebo (P = 0.0053). One subject on TXE was discontinued from the study after the first exercise test because of secondary heart block during the recovery period. It was concluded that TXE and timolol hemihydrate solution show similar systemic beta-blockade activity when both are dosed once a day.
Adrenergic beta-Antagonists↗
A community approach to health.
Improving the health and well-being of a community may seem like a daunting task-particularly when you consider the vast number of factors that can influence the quality of life of a neighborhood or a region. It's not impossible, however, as six widely different communities across the U.S. are discovering. The Accelerating Community Transformation (ACT) project--now underway by The Healthcare Forum through a five-year, $5 million grant from pharmaceutical joint venture Astra Merck Inc.--is an innovative attempt to create real-life learning laboratories in communities as diverse as an inner-city neighborhood on the west side of Chicago; the small southern town of Aiken, S.C.: the semi-desert city of San Bernardino, Calif.; a corner of America's heartland where Missouri, Kansas. Nebraska and Iowa meet; the new town of Celebration, Fla.; and St. Louis, Mo. The goals: to evaluate and accelerate community-wide efforts that result in healthier, more desirable places for people to live, work and play; to build community capacity; and to achieve measurable improved health and quality of life outcomes.
California↗
A randomized trial in patients inadequately controlled with timolol alone comparing the dorzolamide-timolol combination to monotherapy with timolol or dorzolamide. Dorzolamide-Timolol Combination Study Group.
OBJECTIVE: To compare the dorzolamide-timolol fixed combination twice daily to its components, timolol maleate and dorzolamide hydrochloride, given in their usual monotherapy regimens in patients whose intraocular pressure (IOP) was not controlled on timolol twice daily alone. DESIGN: Parallel, randomized, double-masked, and active-controlled study. PARTICIPANTS: Enrolled were 253 patients from 22 sites throughout the United States. INTERVENTION: After a 3-week run-in of timolol (TIMOPTIC; Merck & Co., Inc., Whitehouse Station, NJ) twice daily, eligible patients received either the combination (COSOPT; Merck & Co., Inc., Whitehouse Station, NJ) twice daily (plus placebo to ensure masking), timolol twice daily (plus placebo to ensure masking), or dorzolamide (TRUSOPT; Merck & Co. Inc., Whitehouse Station, NJ) three times daily for 3 months. MAIN OUTCOME MEASURES: Intraocular pressure taken at hours 0 (trough) and 2 (peak) after week 2 and months 1, 2, and 3 was compared to baseline within each treatment group and between the combination and each component group. The safety profile of the combination was compared to each component. RESULTS: The combination was numerically superior at all study timepoints and was statistically superior at all timepoints except for month 2, hour 0 for timolol, and month 2, hour 2 for dorzolamide. The safety profile of the combination reflected those of its two components. The number of patients reporting ocular or local adverse experiences was greater for the combination (45%) and dorzolamide (45%) than for timolol (27%), with burning and/or stinging eye being the most frequently reported. CONCLUSION: The dorzolamide-timolol combination provides additional IOP lowering compared to either of its individual components and generally is well-tolerated.
Adrenergic beta-Antagonists↗
Comparison of dorzolamide and timolol as suppressors of aqueous humor flow in humans.
OBJECTIVES: To measure the effectiveness of topical 2% dorzolamide hydrochloride (Trusopt, Merck & Co Inc, Whitehouse Station, NJ) as a suppressor of aqueous humor flow in the human eye as compared with the effectiveness of 0.5% timolol maleate (Timoptic, Merck & Co Inc) and to measure the additivity of the 2 drugs. DESIGN: A randomized, double-masked, placebo-controlled study of 40 human subjects was carried out in 2 academic centers (Mayo Clinic, Rochester, Minn, and University of Uppsala, Uppsala, Sweden). The rate of aqueous flow was measured from 8 AM to 4 PM by means of fluorophotometry after administration of doses of each drug singly and both drugs together. RESULTS: Dorzolamide reduced aqueous flow from 3.07 +/- 0.63 microL/min (mean +/- SD) to 2.53 +/- 0.60 microL/min, a reduction of 18% (P < .001). Timolol reduced aqueous flow from the same beginning rate to 1.64 +/- 0.35 microL/min, a reduction of 47% (P < .001). The inhibitory effect of timolol was 2.6 times the inhibitory effect of dorzolamide (P < .001). The 2 drugs were almost completely additive, and together reduced the flow to 1.37 +/- 0.33 microL/min, a reduction of 55%. Consistent effects were observed on intraocular pressure. CONCLUSIONS: Timolol is more effective than dorzolamide as a suppressor of aqueous humor flow in the normal human eye. Timolol and dorzolamide are additive in their effects, both on aqueous flow and intraocular pressure.
Adrenergic beta-Antagonists↗
Acute encephalopathy followed by permanent brain injury or death associated with further attenuated measles vaccines: a review of claims submitted to the National Vaccine Injury Compensation Program.
OBJECTIVE: To determine if there is evidence for a causal relationship between acute encephalopathy followed by permanent brain injury or death associated with the administration of further attenuated measles vaccines (Attenuvax or Lirugen, Hoechst Marion Roussel, Kansas City, MO), mumps vaccine (Mumpsvax, Merck and Co, Inc, West Point, PA), or rubella vaccines (Meruvax or Meruvax II, Merck and Co, Inc, West Point, PA), combined measles and rubella vaccine (M-R-Vax or M-R-Vax II, Merck and Co, Inc, West Point, PA), or combined measles, mumps, and rubella vaccine (M-M-R or M-M-R II, Merck and Co, Inc, West Point, PA), the lead author reviewed claims submitted to the National Vaccine Injury Compensation Program. METHODS: The medical records of children who met the inclusion criteria of receiving the first dose of these vaccines between 1970 and 1993 and who developed such an encephalopathy with no determined cause within 15 days were identified and analyzed. RESULTS: A total of 48 children, ages 10 to 49 months, met the inclusion criteria after receiving measles vaccine, alone or in combination. Eight children died, and the remainder had mental regression and retardation, chronic seizures, motor and sensory deficits, and movement disorders. The onset of neurologic signs or symptoms occurred with a nonrandom, statistically significant distribution of cases on days 8 and 9. No cases were identified after the administration of monovalent mumps or rubella vaccine. CONCLUSIONS: This clustering suggests that a causal relationship between measles vaccine and encephalopathy may exist as a rare complication of measles immunization.
Acute Disease↗
Reactogenicity and immunogenicity of a new live attenuated combined measles, mumps and rubella vaccine in healthy children.
OBJECTIVE: To compare the reactogenicity and immunogenicity of a novel live attenuated measles-mumps-rubella vaccine, SB MMR (Priorix; SmithKline Beecham Biologicals), with a widely used MMR vaccine, Merck MMR (M-M-R II; Merck & Co. Inc). METHODS: A total of 4702 healthy children, ages 9 to 24 months, were enrolled in 8 single blind, randomized, controlled trials. Reactogenicity (local and general solicited symptoms and all unsolicited symptoms) was assessed for up to 42 days postvaccination. Immunogenicity [seroconversion rates and geometric mean titers (GMT)] was assessed at 42 or 60 days postvaccination in 1912 subjects in 7 studies. In two studies the persistence of the antibodies at Month 12 postvaccination was assessed in 201 subjects. RESULTS: Local symptoms (pain on or immediately after injection; pain, redness and swelling within 4 days of injection) were reported less frequently after SB MMR than Merck MMR (P < 0.0001). General symptoms and all other events were similar between the two groups. Fever >39.5 degrees C was reported after 9.5 and 11.9% of the SB MMR and Merck MMR doses, respectively. At Days 42 to 60 postvaccination seroconversion rates for antimeasles antibodies were higher with SB MMR than with Merck MMR (98.7% vs. 96.9%, P < 0.031) but similar in both groups for anti-mumps and anti-rubella antibodies, GMTs being approximately 10% higher (P < 0.05) with Merck MMR than with SB MMR. At the Month 12 assessment the seropositivity rates and GMTs were similar in both groups. CONCLUSION: When administered as primary vaccination in children in the second year of life, the new SB MMR vaccine has been shown to be superior to a comparator vaccine in terms of local reactogenicity, with equivalent immunogenicity.
Analysis of Variance↗
Aqueous humor flow in human eyes treated with dorzolamide and different doses of acetazolamide.
OBJECTIVE: To measure the effect of topically applied 2% dorzolamide hydrochloride (Trusopt, Merck & Co Inc, Whitehouse Station, NJ) and different doses of orally administered acetazolamide (Diamox, Lederle Ophthalmic Pharmaceuticals, Pearl River, NY), alone and in combination, on aqueous humor flow. DESIGN: A randomized, double-masked, placebo-controlled study of 20 human subjects was carried out. Aqueous humor flow was measured by clearance of topically applied fluorescein. Serum standard bicarbonate and serum acetazolamide levels were analyzed. RESULTS: Treatment with dorzolamide reduced aqueous flow by 17%, and a maximum dose of acetazolamide alone reduced flow by 29%. Increasing doses of acetazolamide alone gradually decreased flow, while small doses of acetazolamide did not suppress flow further when dorzolamide was already applied topically. Serum acetazolamide concentrations rose with increasing doses of acetazolamide. Serum standard bicarbonate levels were all in the normal range. CONCLUSIONS: Treatment with dorzolamide reduced aqueous humor flow statistically significantly (2.50 microL/min vs 3.00 microL/min; P=.001) compared with placebo, but less than a maximum dose ofacetazolamide. Small doses of acetazolamide added to dorzolamide treatment did not further enhance the decrease in flow. Since there was no metabolic acidosis as measured by plasma levels of standard bicarbonate, the decrease in aqueous flow could be attributed to the direct action of the carbonic anhydrase inhibitors on the carbonic anhydrase enzymes. It is concluded that the smaller effect of dorzolamide, as compared with acetazolamide, is due to insufficient inhibition of at least 1 of the 2 carbonic anhydrase isozymes involved in aqueous humor production.
Acetazolamide↗
Use of doxorubicin and dacarbazine for the management of unresectable intra-abdominal desmoid tumors in Gardner's syndrome.
PURPOSE: The aim of this study was to describe the natural history and management of surgically unresectable intra-abdominal desmoid tumors in two patients with Gardner's syndrome from two unrelated families, where each had failed on conventional therapy. METHODS: Two patients with Gardner's syndrome were placed on a chemotherapy regimen which included doxorubicin (90 mg/m2) and dacarbazine (900 mg/m2) in divided doses over four days of continuous infusion. Their progress on chemotherapy was assessed by abdominal computerized tomography and laparoscopy. RESULTS: The computerized abdominal tomography scans proved difficult to interpret because of adhesions and matted small bowel resulting from the patients original colectomies. These findings made it difficult to differentiate postoperative changes from residual desmoid tumor. Second-look laparotomy in such patients was contraindicated as this may predispose to further desmoid production. Laparoscopy disclosed a complete response to this chemotherapy. Nevertheless, we had an iatrogenic small bowel perforation in one of these patients. Each patient showed a complete response to chemotherapy. CONCLUSION: Surgical resection remains the first-line treatment of intraabdominal desmoid tumors. However, doxorubicin/dacarbazine chemotherapy on a clinical trial basis may be indicated in patients whose intra-abdominal desmoid is unresectable, or who have failed to respond to treatment with hormones (tamoxifen, Toremifene), steroids (prednisone), and nonsteroidal anti-inflammatory agents (Clinoril; Merck & Co., Inc., West Point, PA).
Adult↗
Management of desmoid tumors in patients after ileal pouch-anal anastomosis for familial adenomatous polyposis.
PURPOSE: The aim of this study was to review the management of desmoid tumors in patients who have undergone ileal pouch-anal anastomosis for familial adenomatous polyposis and their outcome. METHODS: A retrospective review of case notes was undertaken in a series of 196 patients with familial adenomatous polyposis who had had an ileal pouch-anal anastomosis. Eleven patients were identified in whom desmoid tumor had developed (4 male; median age, 30 (range, 16-43) years). RESULTS: Desmoid tumors developed in the abdominal wall alone in 4 of 11 patients. Three enlarging tumors were resected with no subsequent recurrence. No patient received adjuvant treatment and pouch function remained stable at a median follow-up of eight years. Mesenteric desmoid tumors developed in seven patients; the pouch has been excised in two because of ischemia; two other patients have had defunctioning stomas created because of slow progression of their desmoid tumors. One patient had a single-lumen pouch excised and a new S-pouch inserted, with no subsequent recurrence of the desmoid tumor, and in two patients the mesenteric desmoid tumor has remained unchanged. All of these patients received long-term Clinoril (sulindac, Merck & Co., Inc., West Point, PA). Although there has been no significant deterioration in pouch function in patients in whom the pouch remains in situ, the pouch function was significantly worse compared with a control group of patients after ileal pouch-anal anastomosis for familial adenomatous polyposis in whom desmoid tumors did not develop. CONCLUSION: Desmoid tumors developed in 5.6 percent of 196 patients after ileal pouch-anal anastomosis for familial adenomatous polyposis. No patient with abdominal-wall desmoid tumor had a recurrence after local excision. By contrast, mesenteric desmoid tumors eventually resulted in pouch failure in four of seven affected patients.
Abdominal Muscles↗
Comparative study of reactogenicity and immunogenicity of new and established measles, mumps and rubella vaccines in healthy children.
Concerns about the association of aseptic meningitis with measles-mumps-rubella (MMR) vaccines containing the Urabe Am 9 strain and the increasing worldwide demand for MMR vaccines, prompted the development of a new mumps vaccine strain (RIT 4385) by SmithKline Beecham Biologicals (SB) as part of a trivalent live attenuated MMR vaccine. The present study assessed the immunogenicity and reactogenicity of two lots of 'Priorix' with a widely used and established vaccine M-M-R II (Merck & Co. Inc.) as comparator vaccine. 255 healthy children, 12 to 24 months of age, were enrolled in a single-blind study and randomly allocated to receive a single dose of one of two lots of "Priorix" or M-M-R II vaccine. Vaccinees were followed up for six weeks post-vaccination for solicited and unsolicited symptoms. Immunogenicity was determined in pre- and 60 days post-vaccination sera using commercial immunoassays for measles, mumps and rubella antibodies. There were no significant differences in immune responses between groups for any of the three vaccine components. In initially seronegative subjects, the respective post-vaccination seroconversion rates for 'Priorix' lots 1 and 2, and M-M-R II were 100, 100 and 97.6% for measles antibodies, 91.7, 95.1 and 94% for mumps antibodies and 100, 100 and 100% for rubella antibodies, respectively. GMTs for the three groups were 3,076, 3,641 and 3,173 mIU/ml for measles antibodies, 934, 900 and 1,043 U/ml for mumps antibodies, and 86.4, 87.5 and 97.1 IU/ml for rubella antibodies, respectively. The incidence of local symptoms was significantly lower for both 'Priorix' lots (17.6 and 15.3% for lots 1 and 2, respectively) than for M-M-R II (37.6%). Fever > or = 38.1 degrees C during the six-week observation period occurred in approximately 25% of all subjects in all groups with no differences between the groups. No parotid/salivary gland swelling or signs of suspected meningism were reported, and there were no serious adverse events related to vaccination. The new MMR vaccine 'Priorix' containing the new RIT 4385 mumps strain was safe and had a significantly improved local tolerability profile over the comparator vaccine, M-M-R II, while eliciting an at least equivalent immune response.
Antibodies, Viral↗
Uveitis associated with varicella virus vaccine.
PURPOSE: To report a case of uveitis associated with the live attenuated varicella virus vaccine (Varivax; Merck & Co, Inc, West Point, Pennsylvania) in a young, otherwise healthy girl. METHODS: The time of onset of uveitis in relation to vaccination and the number and the pattern of distribution of vesicles were noted. The patient received oral acyclovir and topical steroids and cycloplegic drops. RESULTS: The uveitis and vesicular rash improved significantly after 7 days of treatment. A literature review and communications with the drug's manufacturer disclosed no identifiable previous cases of uveitis associated with Varivax. CONCLUSIONS: Uveitis should be recognized as a possible adverse side effect of the varicella vaccine.
Acyclovir↗
Comparison of utilization of Sinemet and Parkinson's disease mortality as surrogate indicators of Parkinson's disease in the United States.
OBJECTIVE: To compare two surrogate indicators of population disease burden for Parkinson's disease: utilization of Sinemet and Parkinson's disease mortality. DESIGN: National Center for Health Statistics data were used to tabulate Parkinson's disease mortality in the United States by state for 1987-1989. Sinemet sales data by state were obtained from Merck & Co., Inc. for 1988. Least squares regression analyses were used to assess the relationship between Sinemet utilization and Parkinson's disease mortality. SETTING: United States. RESULTS: Regression analyses showed extraordinarily strong associations between state-level Parkinson's disease mortality and Sinemet utilization (underlying-cause model r2 = 0.969, p = 0.0001; multiple-cause model r2 = 0.980, p = 0.0001). CONCLUSIONS: Sinemet utilization very closely parallels Parkinson's disease mortality, suggesting that Sinemet utilization and Parkinson's disease mortality are both useful indices of the population burden of Parkinson's disease for large-scale epidemiological studies.
Antiparkinson Agents↗
Correlation of fermentation yield with yeast extract composition as characterized by near-infrared spectroscopy
Complex, ill-defined mixtures of natural origin are often used as nutrients in the production of biological products through microbial fermentation. Product yields are affected by variation in these natural products. It was desired to examine near-infrared spectroscopy as a rapid screening tool for qualifying raw material lots. Specifically, the characterization of yeast extract was investigated. The model system consisted of a Merck & Co., Inc., microbial fermentation process. Cell mass and specific product yields are dependent upon variations in the yeast extract used in the medium. Partial least-squares regression on the second-derivative spectral absorbances of various yeast extracts in the ranges 1150-1380, 1554-1826, and 2100-2300 nm resulted in the development of models with multiple correlation coefficients of 0.99 for cell mass yields and 0.96 for specific product yields in large-scale fermentations. These models could also be used to predict cell mass yields in 15 L batch fermentations and specific product yields in 2-L shake flasks.
Journal Article↗
Biosynthesis of the 5-Isoxazolidinone-Containing Hexacyclic Structure of Parnafungin.
Parnafungins A-D (1-4) are fungal natural products that inhibit eukaryotic poly(A)-polymerase and were first discovered by Merck & Co., Inc., through a Candida albicans Fitness Test (CaFT) screening program. The biological activity of parnafungins is a result of the unique fused hexacyclic structure highlighted by a 5-isoxazolidinone (5ILD) N-heterocycle. In this work, we characterize the complete biosynthetic pathway of parnafungins through heterologous reconstitution and enzymatic assays. Nearly half of the 26-gene biosynthetic gene cluster of parnafungin is responsible for the production of a known polyketide natural product, blennolide C. Starting from the blennolide C fragment, a three-enzyme cascade involving CoA-ligase ParJ, P450 ParO, and DUF829 ParD catalyzes the formal biaryl cross-coupling between blennolide C and anthranilate. Subsequent oxidative cyclization generates a phenanthridine product that is then reduced by atypical short-chain reductase ParT. N-Hydroxylation by flavin-dependent monooxygenase ParB and subsequent lactonization catalyzed by a homologue of dienenolactone hydrolase ParF form the 5ILD ring and complete the biosynthesis of 1 and 2. Methylation of 1 forms parnafungin C (3), and lastly epoxidation forms parnafungin D (4). Together, our work revealed the chemical logic and enzymology in extending the biosynthetic pathway of a well-characterized natural product, blennolide C, to introduce considerable additional structural diversity that affords parnafungins with unique biological activity.
Molecular Structure↗