- Email: [email protected]
Oral immunization as a strategy for enhancing corneal allograft survival
retrospective review of the Drug Safety Clinic and the Health Protection Branch databases and a literature review was conducted by the authors to determine if similar rare events are associated with tetracycline and doxycycline. Cases of isolated single organ dysfunction (SOD) attributable to the use of these antibiotics were also identified. Approximately 1,866,OOO prescriptions for these antibiotics were filled during 1994 in Canada. Nineteen cases of HSR due to minocycline, two due to tetracycline, and one due to doxycycline were identified. Eleven cases of SSLR due to minocycline, three due to tetracycline, and two due to doxycycline were identified. All 33 cues of druginduced lupus were attributable to minocycline. Forty cases of SOD from minocycline, 37 cases from tetracycline, and six from doxycycline were detected. Hypersensitivity syndrome reaction, SSLR, and SOD occur on average within 4 weeks of therapy, whereas minocycline-induced lupus occurs on average 2 years after the initiation of therapy. The authors conclude that early serious events occurring during the course of tetracycline antibiotic treatment include HSR, SSLR, and SOD. Drug-induced lupus, which occurs late in the course of therapy, is reported only with minocylcine. The authors theorize that minocycline metabolism may account for the increased frequency of serious adverse events with this drug. - Thomas J Liesegang
protein gG-2 and HSV-2. From 1988 to 1994, the seroprevalence of HSV-2 in persons aged 12 years or older in the United States was 21.9% (95% confidence interval [CI], 20.2% to 23.6%), corresponding to 45 million infected people in the noninstitutionalized civilian population. The seroprevalence was higher among women (25.6%) than men (17.8%) and higher among blacks (45.9%) than whites ( 17.6%). Less than 10% of all those who were seropositive reported a history of genital herpes infection. In a multivariate model, the independent predictors of HSV-2 seropositivity were female sex, black race, or Mexican-American ethic background, older less education, poverty, cocaine use, and a age, greater lifetime number of sexual partners. Compared with the period from 1976 to 1980, the age-adjusted seroprevalence of HSV-2 rose 30% (95% CI, 15.8% to 45.8%). Th e seroprevalence quintupled among white teenagers and doubled among whites in their twenties. Among blacks and older whites, the increases were smaller. The authors suggest improvements in the prevention of HSV infections are needed, particularly because genital ulcers may facilitate the transmission of the human immunodeficiency virus. - Thomas J. Liesegang “Division of STD Prevention, National Center for HIV, STD and TB Prevention, Centers for Disease Control and Prevention, Mailstop B-02, 1600 Clifton Rd, Atlanta, GA 30333.
*Drug Safety Research Group, Sunnybrook Health Science Centre, Room E240, 2075 Bayview Ave, Toronto, Ontario, Canada M4N 3M5.
Oral immunization as a strategy for enhancing cornea1 allograft survival. Ma D, Mellon J, l
Herpes simplex virus type 2 in the United States, 1976 to 1994. Fleming DT, McQuillan GM, Johnson RE, Nahmias AJ, Aral SO, Lee FK, St Louis ME*. N Engl J Med 1997;337:1105-1111.
l
T
HE AUTHORS
INVESTIGATED
THE SEROPREVALENCE
and correlates of HSV-2 infection in the United States and identified changes in HSV-2 seroprevalence since the late 1970s. Serum samples and questionnaire data were collected during the National Health and Nutrition Examination Surveys II (19761980) and III (1988-1994). HSV-2 antibody was assessed with an immunodot assay specific for glyco-
282
AMERICAN
JOURNAL
Neiderkorn
T
JY*. Br J Ophthalmol
1997;81:778-784.
HE AUTHORS USED A MOUSE MODEL OF PENETRAT-
ing keratoplasty to evaluate the efficacy and optimal conditions for preventing immunologic rejection of cornea1 allografts through oral administration of donor specific cornea1 cells. C3H cornea1 grafts were transplanted orthotopically to CB6FI recipients and represented mismatches at the entire major histocompatibility complex (MHC) and multiple minor histocompatibility loci. Tissue-cultured C3H corneal epithelial and endothelial cells were administered orally to CB6FI mice before or shortly after the
OF OPHTHALMOLOGY
FEBRUARY
I 998
application of orthotopic C3H cornea1 allografts. Cultured C3H cornea1 cells were conjugated with the nontoxic B subunit of cholera toxin as a means of preferentially inducing oral tolerance. Ten oral doses of donor cells administered before keratoplasty re, duced the incidence of cornea1 graft rejection from 100% in untreated hosts to 54% in orally tolerized mice. Conjugation of cholera toxin to cornea1 cells significantly enhanced the efficacy of oral tolerance such that only 9% of the mice fed 10 doses of cholera toxin conjugated cells rejected their cornea1 grafts. Even a single oral inoculation of cornea1 cells conjugated to cholera toxin was able to reduce cornea1 graft rejection by 36%. The authors conclude that oral administration of donor-specific cells greatly enhances cornea1 graft survival Use of cholera toxin adjuvant markedly enhances the efficacy of oral tolerance such that even a single oral dose of donor cells significantly reduces the clinical feasibility of this novel strategy for preventing immunologic rejection of cornea1 transplants. - Thomas J. Liesegang *Department 5323 Harry
of Ophthalmology, UT Southwestern Hines Rlvd, Dallas, TX 752359057.
Medical
Center,
Reduction by anti-inflammatory drugs of the response of cornea1 sensory nerve fibers to chemical irritation. Chen X, Gallar J, Belmonte C*. Invest
l
Ophthalmol
N
Vis Sci 1997;38:1944-1953.
ONSTEROIDAL
ANTIFLAMMATORY
DRUGS
(NSAIDS)
have been applied topically to reduce ocular pain caused by cornea1 injury or anterior segment surgery. The authors investigated whether the analgesic effects of the NSAIDs diclofenac, indomethacin, and flurbi-
VOL.
125,
No.
2
profen and of the calcium channel antagonist diltiazem on cornea1 pain are mediated by a reduction of nerve activity in cornea1 polymodal nociceptive fibers. Impulse activity of single A.6 and C cornea1 nerve fibers was recorded from the ciliary nerves of anesthetized cats. Polymodal units were identified by their response to both touching with the CochetBonnet esthesiometer and to acidic stimulation with 30-second pulses of 80% or 98.5% CO, or 60 ~1 of 10 mM acetic acid, applied to the cornea1 receptive area. Ongoing impulse activity, firing responses to CO, or acetic acid, and mechanical threshold of single fibers were recorded before and at various times (5 to 90 minutes) after topical application of 0.1% sodium diclofenac, 0.03% sodium flurbiprofen, 0.1% indomethacin, and 0.045% diltiazem hydrochloride or of their vehicles. Indomethacin, diclofenac, and flurbiprofen, in decreasing order of potency, gradually reduced the mean frequency of the impulse response of cornea1 polymodal nerve fibers evoked by CO, stimuli. The progressive increase of ongoing activity, observed in vehicle-treated eyes after repeated CO, stimulation was also prevented by NSAIDs. Diltiazem also attenuated the response to CO, for a shorter period of time and with a faster time course. The mechanical threshold of cornea1 polymodal fibers was not affected by treatment with any of these drugs. The authors conclude that there is a direct effect of these drugs on the excitability of polymodal nerve endings but also an inhibition by NSAIDs of the formation of cyclooxygenase products such as prostaglandin, thus reducing the enhanced responsiveness of nociceptors caused by local release of arachidonic acid metabolites from injured cells. - Thomas J Liesegang *Institute de Neurosciencias, Campus de San Juan, Universidad Hernandez, Ctra. National 332 s/n, 03550 San Juan, Spain.
ABSTRACTS
Miguel
283
protein gG-2 and HSV-2. From 1988 to 1994, the seroprevalence of HSV-2 in persons aged 12 years or older in the United States was 21.9% (95% confidence interval [CI], 20.2% to 23.6%), corresponding to 45 million infected people in the noninstitutionalized civilian population. The seroprevalence was higher among women (25.6%) than men (17.8%) and higher among blacks (45.9%) than whites ( 17.6%). Less than 10% of all those who were seropositive reported a history of genital herpes infection. In a multivariate model, the independent predictors of HSV-2 seropositivity were female sex, black race, or Mexican-American ethic background, older less education, poverty, cocaine use, and a age, greater lifetime number of sexual partners. Compared with the period from 1976 to 1980, the age-adjusted seroprevalence of HSV-2 rose 30% (95% CI, 15.8% to 45.8%). Th e seroprevalence quintupled among white teenagers and doubled among whites in their twenties. Among blacks and older whites, the increases were smaller. The authors suggest improvements in the prevention of HSV infections are needed, particularly because genital ulcers may facilitate the transmission of the human immunodeficiency virus. - Thomas J. Liesegang “Division of STD Prevention, National Center for HIV, STD and TB Prevention, Centers for Disease Control and Prevention, Mailstop B-02, 1600 Clifton Rd, Atlanta, GA 30333.
*Drug Safety Research Group, Sunnybrook Health Science Centre, Room E240, 2075 Bayview Ave, Toronto, Ontario, Canada M4N 3M5.
Oral immunization as a strategy for enhancing cornea1 allograft survival. Ma D, Mellon J, l
Herpes simplex virus type 2 in the United States, 1976 to 1994. Fleming DT, McQuillan GM, Johnson RE, Nahmias AJ, Aral SO, Lee FK, St Louis ME*. N Engl J Med 1997;337:1105-1111.
l
T
HE AUTHORS
INVESTIGATED
THE SEROPREVALENCE
and correlates of HSV-2 infection in the United States and identified changes in HSV-2 seroprevalence since the late 1970s. Serum samples and questionnaire data were collected during the National Health and Nutrition Examination Surveys II (19761980) and III (1988-1994). HSV-2 antibody was assessed with an immunodot assay specific for glyco-
282
AMERICAN
JOURNAL
Neiderkorn
T
JY*. Br J Ophthalmol
1997;81:778-784.
HE AUTHORS USED A MOUSE MODEL OF PENETRAT-
ing keratoplasty to evaluate the efficacy and optimal conditions for preventing immunologic rejection of cornea1 allografts through oral administration of donor specific cornea1 cells. C3H cornea1 grafts were transplanted orthotopically to CB6FI recipients and represented mismatches at the entire major histocompatibility complex (MHC) and multiple minor histocompatibility loci. Tissue-cultured C3H corneal epithelial and endothelial cells were administered orally to CB6FI mice before or shortly after the
OF OPHTHALMOLOGY
FEBRUARY
I 998
application of orthotopic C3H cornea1 allografts. Cultured C3H cornea1 cells were conjugated with the nontoxic B subunit of cholera toxin as a means of preferentially inducing oral tolerance. Ten oral doses of donor cells administered before keratoplasty re, duced the incidence of cornea1 graft rejection from 100% in untreated hosts to 54% in orally tolerized mice. Conjugation of cholera toxin to cornea1 cells significantly enhanced the efficacy of oral tolerance such that only 9% of the mice fed 10 doses of cholera toxin conjugated cells rejected their cornea1 grafts. Even a single oral inoculation of cornea1 cells conjugated to cholera toxin was able to reduce cornea1 graft rejection by 36%. The authors conclude that oral administration of donor-specific cells greatly enhances cornea1 graft survival Use of cholera toxin adjuvant markedly enhances the efficacy of oral tolerance such that even a single oral dose of donor cells significantly reduces the clinical feasibility of this novel strategy for preventing immunologic rejection of cornea1 transplants. - Thomas J. Liesegang *Department 5323 Harry
of Ophthalmology, UT Southwestern Hines Rlvd, Dallas, TX 752359057.
Medical
Center,
Reduction by anti-inflammatory drugs of the response of cornea1 sensory nerve fibers to chemical irritation. Chen X, Gallar J, Belmonte C*. Invest
l
Ophthalmol
N
Vis Sci 1997;38:1944-1953.
ONSTEROIDAL
ANTIFLAMMATORY
DRUGS
(NSAIDS)
have been applied topically to reduce ocular pain caused by cornea1 injury or anterior segment surgery. The authors investigated whether the analgesic effects of the NSAIDs diclofenac, indomethacin, and flurbi-
VOL.
125,
No.
2
profen and of the calcium channel antagonist diltiazem on cornea1 pain are mediated by a reduction of nerve activity in cornea1 polymodal nociceptive fibers. Impulse activity of single A.6 and C cornea1 nerve fibers was recorded from the ciliary nerves of anesthetized cats. Polymodal units were identified by their response to both touching with the CochetBonnet esthesiometer and to acidic stimulation with 30-second pulses of 80% or 98.5% CO, or 60 ~1 of 10 mM acetic acid, applied to the cornea1 receptive area. Ongoing impulse activity, firing responses to CO, or acetic acid, and mechanical threshold of single fibers were recorded before and at various times (5 to 90 minutes) after topical application of 0.1% sodium diclofenac, 0.03% sodium flurbiprofen, 0.1% indomethacin, and 0.045% diltiazem hydrochloride or of their vehicles. Indomethacin, diclofenac, and flurbiprofen, in decreasing order of potency, gradually reduced the mean frequency of the impulse response of cornea1 polymodal nerve fibers evoked by CO, stimuli. The progressive increase of ongoing activity, observed in vehicle-treated eyes after repeated CO, stimulation was also prevented by NSAIDs. Diltiazem also attenuated the response to CO, for a shorter period of time and with a faster time course. The mechanical threshold of cornea1 polymodal fibers was not affected by treatment with any of these drugs. The authors conclude that there is a direct effect of these drugs on the excitability of polymodal nerve endings but also an inhibition by NSAIDs of the formation of cyclooxygenase products such as prostaglandin, thus reducing the enhanced responsiveness of nociceptors caused by local release of arachidonic acid metabolites from injured cells. - Thomas J Liesegang *Institute de Neurosciencias, Campus de San Juan, Universidad Hernandez, Ctra. National 332 s/n, 03550 San Juan, Spain.
ABSTRACTS
Miguel
283