| Category | Hospital/Research Institute |
|---|---|
| Country | USA |
The Leprosy Research Unit (LRU) of the Public Health Service (PHS) Hospital, San Francisco, California, began in 1965, with the award of a research grant from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health. After closure of the PHS Hospital in 1980, the activities of the LRU were transferred, first to St. Mary's Hospital, Daly City, Ca., and then to the Presbyterian Hospital and Medical Center, San Francisco, where its activities continued until 1993, at which time funding by the PHS was terminated. The LRU was headed by Louis Levy, M.D., Ph.D. (1965 - 1976), Theodosia M. Welch, Ph.D. (1977 - 1978), James L. Krahenbuhl, Ph.D. (1979 - 1980), and Robert H. Gelber, M.D. (1981 - 1993). Below, the principal activities of the LRU are summarized, and the relevant bibliography is presented.
1965 - 1976
During the period 1965 - 1976, the activities of the LRU were concentrated in four areas: clinical trials among patients with multibacillary leprosy; experimental mycobacterial infections of mice, particularly by Mycobacterium leprae; studies of dapsone; and screening compounds for activity against M. leprae. In addition, a variety of clinical and other studies were carried out.
Clinical trials
A number of important clinical trials, designed in collaboration with C.C. Shepard, Communicable Disease Center, Atlanta, were carried out among patients with MB leprosy. Short-term trials of dapsone, clofazimine and rifampicin, involving small numbers of patients, were carried out among patients under treatment by the Leprosy Clinic of the PHS Hospital (51, 52, 67, 69-71). Biopsy specimens were obtained before treatment and at intervals during treatment, and air-shipped to Atlanta, where M. leprae were recovered from the specimens and inoculated into mice to assess the viability of the organisms. The important findings of these trials were that: dapsone was slowly bactericidal against M. leprae, rendering most of the organisms incapable of multiplying in mice in the course of three months; treatment with clofazimine killed M. leprae resistant to dapsone at approximately the same rate as treatment with dapsone killed drug-susceptible organisms; and treatment with acedapsone killed M. leprae much more slowly, although the response among a few patients was as rapid as that to dapsone. Most important were the trials of rifampicin, which demonstrated that single doses of the drug were capable of killing most of the patient's M. leprae virtually immediately - i.e., by no more than three days after administration of the dose, the patients' organisms had been rendered incapable of multiplication in mice.
In addition to the trials conducted in San Francisco, trials of dapsone, acedapsone, clofazimine and rifampicin, designed by Shepard and Levy, and sponsored by the U.S. Leprosy Panel of the U.S. - Japan Cooperative Medical Science Program, were carried out among larger numbers of MB patients in Cebu, the Philippines, in collaboration with the Leonard Wood Memorial (3-6). For these trials, the identity of results of the mouse foot pad technique in San Francisco and Atlanta was established (53), the mouse foot pad technique was set up in Cebu, after Dr. E.C. dela Cruz had been trained in San Francisco, and mice were inoculated both in Cebu and in San Francisco, in the latter case with organisms recovered from biopsy specimens that had been air-shipped from Cebu. Among the important findings of the trials in Cebu was that the daily administration of clofazimine was more effective than the intermittent administration of the drug in the same total dosage, but that clofazimine administered in a dosage of 1200 mg. once monthly was clearly bactericidal.
Experimental infection
A second, important area of activity of the LRU involved studies of the experimental mycobacterial infection of the mouse and the rat, particularly by M. leprae. Studies were undertaken of: the mouse foot pad technique itself; the immune response of the mouse to infection by M. leprae; and, in collaboration with A.H. Fieldsteel,* Stanford Research Institute (SRI), Menlo Park, Ca., M. leprae infection of the neonatally thymectomised rat and its response to antimicrobial treatment (12-15). In addition, a few studies of M. lepraemurium and M. marinum infections of the mouse were carried out (46, 55-57). Finally, work was carried out in the area of heterologous immunity, some of this in collaboration with J.L. Krahenbuhl and J.S. Remington, Palo Alto Medical Research Foundation, Palo Alto, Ca (20).
The majority of organisms inoculated into the mouse foot pad could not be recovered shortly after inoculation, suggesting that multiplication of the organisms proceeded from only the small fraction of the inoculum that remained in situ. Employing a technique independent of the growth curve of M. leprae in the mouse foot pad, the doubling time of the organism was found to be approximately 11 days, significantly shorter than the estimate of approximately two weeks that had been derived from measurements of the slope of the growth curve during logarithmic multiplication (21, 29, 43, 44). The M. leprae-infected mouse was shown to resist superinfection if the second challenge were delivered at least 30 days after the first, but to be incapable of resisting a second challenge delivered only 15 days after initial infection (27). In addition, the immunologically intact mouse was found to kill the resident M. leprae with a half-time of disappearance of approximately 18 days, once the maximum of multiplication of the organisms had been achieved (72). Finally, work carried out in collaboration with M.J. Evans, SRI, demonstrated that the bulk of organism-bearing macrophages that characterized the lesion of mice infected in the foot pad were generated within the lesion itself (9, 11).
Studies of dapsone
A number of antimicrobial, metabolic and pharmacologic studies of dapsone were carried out both in the LRU (1, 23, 25, 38, 58, 66) and in collaboration with J.H. Peters, SRI (2, 16, 17, 36, 45, 47, 48, 59-65). These studies focused on the minimal inhibitory concentration of dapsone, the metabolism of the drug in man and several experimental animals, the polymorphic acetylation of dapsone, protein-binding of the drug and of monoacetyldapsone, its primary metabolite, and the bactericidal properties of the drug.
Drug-screening
Drugs of a number of classes were screened for activity against M. leprae by administration of the drugs to M. leprae-infected mice (28, 30-35, 40-42, 54). Chief among the drug classes were analogues of dapsone and clofazimine, antithyroid drugs, inducers of interferon, and the unique acids of chaulmoogra oil.
Miscellaneous studies
In the area of clinical studies, the efficacy of thalidomide in the treatment and prevention of erythema nodosum leprosum (ENL) was studied in collaboration with P. Fasal, PHS Hospital, San Francisco, and N. Levan and R.I. Freedman, University of Southern California, Los Angeles (37). The prevalence of secondary dapsone-resistant leprosy in Israel was studied in collaboration with J. Sheskin, Ministry of Health, Jerusalem, Israel (50). Finally, D.J. Drutz, then of the LRU, carried out studies of the viability of blood-borne M. leprae among patients with M. leprae bacteremia, and of the antimicrobial function of peripheral blood mononuclear cells of patients with leprosy (7, 8).
In the area of pharmocologic studies, work was carried out on the pharmacological properties of clofazimine (26, 49), and on the mechanism of the antimicrobial action of hydnocarpic acid (18, 19).
Finally, several studies of the properties of M. leprae itself were carried out, either in the LRU (22, 24, 39) or as collaborative studies (10, 68).
Partial Bibliography (1965 – 1980)
1. JT Biggs, L Levy. "Binding of dapsone and monoacetyldapsone by human plasma proteins." Proc Soc Exp Biol Med 137 (1971): 692.
2. JT Biggs, AK Uher, L Levy, GR Gordon, JH Peters. "Renal and biliary disposition of dapsone in the dog." Antimicrob Ag Chemother 7 (1975): 816.
3. "Collaborative effort of the US Leprosy Panel (US-Japan Cooperative Medical Science Program) and the Leonard Wood Memorial. Rifampin therapy of lepromatous leprosy." Am J Trop Med Hyg 24 (1975): 475.
4. "Collaborative effort of the US Leprosy Panel (US-Japan Cooperative Medical Science Program) and the Leonard Wood Memorial. Spaced clofazimine therapy of lepromatous leprosy." Am J Trop Med Hyg 25 (1976): 437.
5. "Collaborative effort of the US Leprosy Panel (US-Japan Cooperative Medical Science Program) and the Leonard Wood Memorial. A statistical analysis of two chemotherapy trials in lepromatous leprosy. The response to therapy as measured by mouse inoculation." Am J Trop Med Hyg 27 (1978): 1005.
6. "Collaborative effort of the US Leprosy Panel (US-Japan Cooperative Medical Science Program) and the Leonard Wood Memorial. A statistical analysis of two chemotherapy trials in lepromatous leprosy. II. Interactions among patient variables." Am J Trop Med Hyg 27 (1978): 1015.
7. DJ Drutz, MJ Cline, L Levy. "Leucocyte antimicrobial function in patients with leprosy." J Clin Invest 53 (1974): 380.
8. DJ Drutz, SM O'Neill, L Levy. "The viability of blood-borne Mycobacterium leprae." J Infect Dis 130 (1974): 288.
9. MJ Evans, L Levy. "Ultrastructural changes in cells of the mouse foot pad infected with Mycobacterium leprae." Infect Immun 5 (1972): 238.
10. MJ Evans, L Levy. "Failure of Mycobacterium leprae to incorporate 3H-thymidine administered in vivo." Leprosy Rev 48 (1977): 27.
11. MJ Evans, HE Newton, L Levy. "Early response of the mouse foot pad to Mycobacterium leprae." Infect Immun 7 (1973): 76.
12. AH Fieldsteel, L Levy. "Dapsone chemotherapy of Mycobacterium leprae infection of the neonatally thymectomised Lewis rat." Am J Trop Med Hyg 25 (1976): 854.
13. AH Fieldsteel, L Levy. "Neonatally thymectomized Lewis rats infected with Mycobacterium leprae: response to primary infection, secondary challenge, and large inocula." Infect Immun 14 (1976): 736.
14. AH Fieldsteel, L Levy. "Multiplication of Mycobacterium leprae from large inocula in neonatally thymectomised Lewis rats." Int J Leprosy 44 (1976): 78.
15. AH Fieldsteel, L Levy. "Combined rifampin and dapsone chemotherapy of Mycobacterium leprae infection of the neonatally thymectomized Lewis rat. Int J Leprosy 48 (1980): 267.
16. RH Gelber, JH Peters, GR Gordon, AJ Glazko, L Levy. "The polymorphic acetylation of dapsone in man." Clin Pharmacol Therap 12 (1971): 225.
17. GR Gordon, JH Peters, DC Ghoul, JF Murray, L Levy, JT Biggs. "Disposition of dapsone and monoacetyldapsone in rats." Proc Soc Exp Biol Med 150 (1975): 485.
18. PL Jacobsen, L Levy. "Mechanism by which hydnocarpic acid inhibits mycobacterial multiplication." Antimicrob Ag Chemother 3 (1973): 373.
19. PL Jacobsen, H Ng, L Levy. "The susceptibility of mycobacteria to hydnocarpic acid." Am Rev Resp Dis 107 (1973): 1022.
20. JL Krahenbuhl, L Levy, JS Remington. "Resistance to Mycobacterium leprae in mice infected with Toxoplasma gondii and Besnoitia jellisoni." Infect Immun 10 (1974): 1068.
21. WM Krushat, KE Schilling, SA Edlavitch, L Levy. "Studies of the mouse foot-pad technique for cultivation of Mycobacterium leprae. 4. Statistical analysis of harvest data". Leprosy Rev 47 (1976): 275.
22. L Levy. "The effect of several rates of freezing and thawing on the viability of Mycobacterium leprae." Cryobiol 6 (1969): 42.
23. L Levy. "Death of Mycobacterium leprae in mice, and the additional effect of dapsone administration." Proc Soc Exp Biol Med 135 (1970): 745.
24. L Levy. "The effect of freezing and storage at -60oC on the viability of Mycobacterium leprae." Crybiol 8 (1971): 574.
25. L Levy. "Prolongation of the lag phase of Mycobacterium leprae by dapsone." Proc Soc Exp Biol Med 139 (1972): 263.
26. L Levy. "Pharmacological studies of clofazimine." Am J Trop Med Hyg 23 (1974): 1097.
27. L Levy. "Superinfection in mice previously infected with Mycobacterium leprae." Infect Immun 11 (1975): 1094.
28. L Levy. "The activity of chaulmoogra acids against Mycobacterium leprae." Am Rev Resp Dis 111 (1975): 703.
29. L Levy. "Studies of the mouse foot-pad technique for cultivation of Mycobacterium leprae. 3. Doubling time during logarithmic multiplication." Leprosy Rev 47 (1976): 103.
30. L Levy. "Activity of a thiadiazole on Mycobacterium leprae." Proc Soc Exp Biol Med 153 (1976): 34.
31. L Levy. "Bactericidal action of dapsone against Mycobacterium leprae in mice." Antimicrob Ag Chemother 9 (1976): 614.
32. L Levy. "Activity of derivatives and analogs of dapsone against Mycobacterium leprae." Antimicrob Ag Chemother 14 (1978): 791.
33. L Levy. "Activity of four clofazimine analogues against Mycobacterium leprae." Leprosy Rev 52 (1981): 23.
34. L Levy, F Aizer, H Ng, TM Welch. "The effects of tilorone on mycobacterial infections of mice." Leprosy Rev 49 (1978): 215.
35. L Levy, JA Anandan. "Further studies of the action of antithyroid drugs on Mycobacterium leprae." Proc Soc Exp Biol Med 158 (1978): 582.
36. L Levy, JT Biggs, GR Gordon, JH Peters. "Disposition of the anti-leprosy drug, dapsone, in the mouse." Proc Soc Exp Biol Med 140 (1972): 937.
37. L Levy, P Fasal, NE Levan, RI Freedman. "Erythema nodosum leprosum." Lancet 2 (1973): 324.
38. L Levy, LJ Higgins. "Dapsone assay based on Schiff base formation." Int J Leprosy 34 (1966): 411.
39. L Levy, C Hom, LP Murray. "Enumeration of Mycobacterium leprae stained with and without prior periodate oxidation." Leprosy Rev 47 (1976): 185.
40. L Levy, TC Merigan. "Failure of an interferon inducer to inhibit multiplication of Mycobacterium leprae." Proc Soc Exp Biol Med 134 (1970): 87.
41. L Levy, TC Merigan. "Inhibition of multiplication of Mycobacterium leprae by polyinosinic: polycytidylic acid." Antimicrob Ag Chemother 11 (1977): 122.
42. L Levy, N Moon. Inhibition of the multiplication of Mycobacterium leprae by methimazole. Am Rev Resp Dis 106 (1972): 917.
43. Levy L, N Moon, LP Murray, SM O'Neill, LE Gustafson, MJ Evans. "Studies of the mouse foot pad technic for cultivation of Mycobacterium leprae. 1. Fate of inoculated organisms." Int J Leprosy 42 (1974): 165.
44. L Levy, LP Murray. "Studies of the mouse foot-pad technique for cultivation of Mycobacterium leprae. 2. The relationship between incubation period and generation time." Leprosy Rev 47 (1976): 13.
45. L Levy, H Ng, MJ Evans, JL Krahenbuhl."Susceptibility of thymectomized and irradiated mice to challenge with several organisms, and the effect of dapsone on infection with Mycobacterium leprae." Infect Immun 11 (1975): 1122.
46. L Levy, H Ng, TM Welch. "Survival of BALB/c mice after intraperitoneal infection with Mycobacterium lepraemurium." Israel J Med Sci 16 (1980): 780.
47. L Levy, JH Peters. "Susceptibility of Mycobacterium leprae to dapsone as a determinant of patient response to acedapsone." Antimicrob Ag Chemother 9 (1976): 102.
48. L Levy, JH Peters. "Some characteristics of the action of dapsone on multiplication of Mycobacterium leprae in the mouse." Leprosy Rev 48 (1977): 237.
49. L Levy, HP Randall. "A study of skin pigmentation by clofazimine." Int J Leprosy 38 (404): 1970.
50. L Levy, GS Rubin, J Sheskin. "The prevalence of dapsone-resistant leprosy in Israel." Leprosy Rev 48 (1977): 107.
51. L Levy, CC Shepard, P Fasal. "Clofazimine therapy of lepromatous leprosy caused by dapsone-resistant Mycobacterium leprae." Am J Trop Med Hyg 21 (1972): 315.
52. L Levy, CC Shepard, P Fasal. "The bactericidal effect of rifampicin on M. leprae in man." Int J Leprosy 44 (1976): 183.
53. L Levy, CC Shepard, LP Murray. "A comparative study of mouse foot pad inoculation of skin biopsy specimens from patients with lepromatous leprosy in San Francisco and Atlanta." Int J Leprosy 38 (1970) 54.
54. L Levy, NM Ullmann. "Inhibition of multiplication of Mycobacterium leprae by several antithyroid drugs." Am Rev Resp Dis 111 (1975): 651.
55. H Ng, PL Jacobsen, L Levy. "Analogy of Mycobacterium marinum disease to Mycobacterium leprae infection in foot pads of mice." Infect Immun 8 (1973): 860.
56. H Ng, TM Welch, M Baras, L Levy. "Protection of mice by intraperitoneal vaccination against challenge in the foot pad with Mycobacterium marinum." Israel J Med Sci 16 (1980): 849.
57. H Ng, TM Welch, L Levy. "Survival of BALB/c mice after intravenous infection with Mycobacterium marinum." Israel J Med Sci 16 (1980): 452.
58. ML Panitch, L Levy. "The action of dapsone on a susceptible strain of Mycobacterium kansasii." Leprosy Rev 49 (1978): 131.
59. JH Peters, GR Gordon, JT Biggs, L Levy. "The disposition of dapsone and monoacetyldapsone in the dog." Proc Soc Exp Biol Med 148 (1975): 251.
60. JH Peters, GR Gordon, DC Ghoul, JG Tolentino, GP Walsh, L Levy. "The disposition of the antileprotic drug dapsone (DDS) in Philippine subjects." Am J Trop Med Hyg 21 (1972): 450.
61. JH Peters, GR Gordon, L Levy, MA Storkan, RR Jacobson, CD Enna, WF Kirchheimer. "Metabolic disposition of dapsone in patients with dapsone-resistant leprosy." Am J Trop Med Hyg 23 (1974): 222.
62. JH Peters, GR Gordon, JF Murray, AH Fieldsteel, L Levy. "Minimal inhibitory concentration of dapsone for Mycobacterium leprae in rats." Antimicrob Ag Chemother 8 (1975): 551.
63. JH Peters, L Levy. "Dapsone acetylation in man: another example of polymorphic acetylation." Ann NY Acad Sci 179 (1971): 660.
64. JH Peters, SC Lin, L Levy. "A rapid qualitative spot test for the detection of dapsone in urine." Int J Leprosy 37 (1969): 46.
65. JH Peters, JF Murray, GR Gordon, L Levy, DA Russell, GC Scott, DR Vincin, CC Shepard. "Acedapsone treatment of leprosy patients: response versus drug disposition." Am J Trop Med Hyg 26 (1977): 127.
66. RW Riley, L Levy. "Characteristics of the binding of dapsone and monoacetyldapsone by serum albumin." Proc Soc Exp Biol Med 142 (1973): 1168.
67. CC Shepard, L Levy, P Fasal. "The death of Mycobacterium leprae during treatment with 4,4'-diaminodiphenylsulfone (DDS). Initial rate in patients." Am J Trop Med Hyg 17 (1968): 769.
68. CC Shepard, L Levy, P Fasal. "The sensitivity to dapsone of Mycobacterium leprae from patients with and without previous treatment." AJTMH 18 (1969): 258.
69. CC Shepard, L Levy, P Fasal. "The death rate of Mycobacterium leprae during treatment of lepromatous leprosy with acedapsone (DADDS)." Am J Trop Med Hyg 21 (1972): 440.
70. CC Shepard, L Levy, P Fasal. "Rapid bactericidal effect of rifampin on Mycobacterium leprae." Am J Trop Med Hyg 21 (1972): 446.
71. CC Shepard, L Levy, P Fasal. "Further experience with the rapid bactericidal effect of rifampin on Mycobacterium leprae." Am J Trop Med Hyg 23 (1974): 1120.
72. TM Welch, RH Gelber, LP Murray, H Ng, SM O'Neill, L Levy. Viability of Mycobacterium leprae after multiplication in mice. Infect Immun 30 (1980): 325.
Entry updated February 2016