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H W Murray

Publications and source records attributed to H W Murray.

At least 37 records · Page 2Linked to original sources
PubMed1999

Treatment of idiopathic CD4 T lymphocytopenia with IL-2.

Idiopathic CD4 T lymphocytopenia (ICL) is an unusual immune defect in which there is an unexplained deficit of CD4 T cells, leading to fungal, parasitic or other serious opportunistic infections. Current treatment efforts are directed at eliminating infections. Here we describe the use of a novel treatment, subcutaneous polyethylene glycol (PEG)-IL-2 injections, in a woman with this disorder, who had chronic severe mycobacterial disease which led to repeated hospitalizations, and advancing respiratory insufficiency. For this patient, PEG-IL-2, 50 000 U/m2, has been given by weekly subcutaneous injections for 5.5 years. This treatment has resulted in marked (and still continuing) long-term immunological improvement with normalized T cell functions and increased CD4 cell numbers. She has had substantial clinical improvement with clearing of mycobacterial disease, reducing hospitalizations and improved lung functions. The improvement seen in this patient suggests that low-dose IL-2 is a safe and practical therapy, which might be useful in other subjects with this potentially serious immune defect.

Aged↗
PubMed1999

Oral treatment of visceral leishmaniasis with miltefosine.

In a pilot trial, 28 days of oral treatment with 100-200 mg miltefosine (hexadecylphosphocholine) per day cured 14 of 15 patients with Indian visceral leishmaniasis (VL). To extend the testing of this regimen, 45 additional subjects with VL, of whom 17 had failed previous antimony therapy, were treated with 100 (N = 17), 150 (N = 18) or 200 (N = 10) mg/day. Enrollment at 200 mg/day was stopped after three subjects in this treatment arm developed reversible but serious (grade-3) adverse reactions. The overall clinical and parasitological responses to miltefosine were rapid, with 40 [89%; 95% confidence interval (CI) = 76%-96%] and 44 (98%; CI = 88%-100%) of the patients apparently cured on days 14 and 28, respectively. The one 'treatment failure' recorded on day 28 (and at 6 months) was a subject lost to follow-up. Those apparently cured by day 28 included six patients (one on 100 mg, two on 150 mg and three on 200 mg/day) removed from treatment on days 7-17 because of grade-3 diarrhoea (two cases), vomiting (two cases), diarrhoea and hepatotoxicity (one case) or nephrotoxicity (one case). Transient, mild-moderate vomiting and/or diarrhoea were common during weeks 1-2 and about 25% of the patients also developed primarily mild, self-limited increases in concentrations of aspartate aminotransferase and creatinine and/or blood urea nitrogen. At a 6-month follow-up, all 44 patients apparently cured at day 28 were considered complete responders (definitive cures), including the six treated for only 7-17 days. These results indicate that 100 mg miltefosine/day for 28 days is a promising oral-treatment regimen for VL cases, including those with antimony-unresponsive infections.

Administration, Oral↗
PubMed1999

Kala-azar as an AIDS-related opportunistic infection.

Visceral leishmaniasis (kala-azar) is a worldwide disseminated protozoal infection primarily transmitted by sand flies. Because host defense against this intracellular infection is T-cell-dependent, kala-azar has predictably joined the list of AIDS-related opportunistic infections in endemic areas. The vast majority of patients with AIDS-associated kala-azar are currently found in southern Europe (the Mediterranean basin, especially Spain in injection drug users); future cases will inevitably arise in other endemic regions including India, East Africa and Sudan, and Brazil. In CD4 cell-deficient HIV-infected individuals, kala-azar likely represents recrudescence of previously controlled asymptomatic infection; in drug users, newly acquired infection may result from transmission via shared needles. Coinfected patients are frequently parasitemic and may show atypical clinical presentations, unusual multi-organ involvement, and absent antileishmanial antibodies. Diagnosis is made by microscopic examination or culture of aspirate or biopsy of any involved tissue (primarily bone marrow) or by blood smear or culture. Conventional treatment (pentavalent antimonials) induces initial remission in about 50% of patients; amphotericin B and its new lipid formulations appear more active. If suppressive maintenance therapy is not used, relapse within 1 year is typical. In AIDS patients with a first episode of visceral kala-azar, up to 25% die within 1 month if treatment is stopped. Optimal primary and secondary prophylaxis for AIDS-related kala-azar remain to be determined; life-long maintenance therapy is becoming an accepted approach.

AIDS-Related Opportunistic Infections↗
PubMed1999

Amphotericin B lipid complex in the management of antimony unresponsive Indian visceral leishmaniasis.

Fifty-eight Indian patients with visceral leishmaniasis who did not respond or relapsed after 30 days of consecutive sodium stibogluconate therapy were randomised to treatment with amphotericin B lipid complex (ABLC) using a total dose of 7.5 or 10 mg/kg. Treatment induced a prompt clinical response in all patients with resolution of fever and regression in spleen size. Fever and chills developed during ABLC infusion, but it diminished with successive infusions. Fourteen days after treatment, 26 of 28 (93%) patients in the 7.5 mg/kg group and all 30 (100%) in the 10 mg/kg group had splenic aspirate parasite density scores of 0 and were considered apparent clinical and parasitologic responders. Four and three patients in the 7.5 and 10 mg/kg groups respectively relapsed during six months of followup; thus, overall 22 of 28 (79%) patients treated with 7.5 mg/kg and 27 of 30 (90%) treated with 10 mg/kg were definitive cures. All initial non-responders and relapses were retreated successfully with higher dose of ABLC. These results confirm the efficacy of short-course ABLC therapy for antimony-unresponsive Indian patients with visceral leishmaniasis. Since treatment with a total dose of 7.5 mg/kg did not appear to increase efficacy (79% vs. 84% induced by 5 mg/kg in a prior study), initial treatment with a total dose of 5 mg/kg followed by retreatment of any non-responders represents a potentially less costly approach in patients who fail antimony therapy. Though high cure rates are achieved with > or = 10 mg/kg total dose of ABLC, treatment using lower doses with retreatment of non-responders or relapses with higher dose can result in considerable savings.

Adolescent↗
PubMed1998

Trial of oral miltefosine for visceral leishmaniasis.

BACKGROUND: There is no effective oral treatment for visceral leishmaniasis (kala-azar), a disseminated intracellular protozoal infection that occurs worldwide. Miltefosine, an alkyl phospholipid developed as an oral antineoplastic agent, is active against visceral infection in animal models. We tested safety, tolerance, and efficacy of miltefosine in kala-azar. METHODS: Oral doses of miltefosine were given to six groups of five Indian men for 28 days: 50 mg every second day (group 1), 100 mg every second day (group 2), 100 mg/day (group 3), 150 mg/day (group 4), 200 mg/day (group 5), and 250 mg/day (group 6). Assessment for apparent cure--taken as an afebrile state with decreased spleen size and a splenic-aspirate parasite-density score of 0--was done on days 14 and 28. Definitive cure at 8 months required a parasite-free bone-marrow aspirate and no clinical evidence of relapse. FINDINGS: 21 of 30 patients were apparently cured on day 14. Transient episodes of vomiting and diarrhoea, were common during weeks 1-2 and were seen in 22 patients. Four other patients in groups 5 and 6 had miltefosine withdrawn after 7-10 days because of vomiting. One patient in group 6 developed renal insufficiency and severe diarrhoea and died on day 21. On day 28, all 29 remaining patients were apparently cured. By 8 months, seven of ten patients in groups 1 and 2 had relapsed; however, 18 of 19 patients treated daily (groups 3-6) appeared to be cured. Among the 21 definitive cures were the four patients treated for 10 days or less and 12 for whom previous therapy with pentavalent antimony had failed. INTERPRETATION: Treatment with miltefosine at 100-150 mg/day for 4 weeks has promise as an effective oral treatment of visceral leishmaniasis including antimony-resistant infection.

Administration, Oral↗
PubMed1998

Rapid accurate field diagnosis of Indian visceral leishmaniasis.

BACKGROUND: A firm diagnosis of visceral leishmaniasis (kala-azar) requires demonstration of the parasite in organ aspirates or tissue biopsy samples. The aim of this prospective study was to assess the diagnostic usefulness of non-invasive testing for antibody to the leishmanial antigen K39 by means of antigen-impregnated nitrocellulose paper strips adapted for use under field conditions. METHODS: One drop of peripheral blood is applied to the hitrocellulose strip. Three drops of test buffer (phosphate-buffered saline plus bovine serum albumin) are added to the dried blood. The development of two visible bands indicates presence of IgG anti-K39. 323 consecutive patients with suspected kala-azar referred to two specialist units in India, and 25 healthy controls, provided fingerstick blood samples for the test. Spleen aspirates were taken from 250 patients. FINDINGS: Kala-azar was confirmed by microscopy of spleen-aspirate smears in 127 patients. The K39 strip test was positive in all 127; the estimated sensitivity was therefore 100% (95% CI 98-100). Four patients had positive strip tests but negative aspirate smears; all four responded to treatment for leishmaniasis. 217 individuals, including the 25 healthy controls, 73 patients with malaria or tuberculosis, and 119 spleen-aspirate-negative patients who had presumed malaria or cirrhosis (79) or no final diagnosis (40), had negative strip-test results. None of the 119 aspirate-negative patients developed evidence of kala-azar during 3-6 months of follow-up. The estimated specificity of the strip test was 98% (95-100; 217/221). INTERPRETATION: Detection of anti-K39 by immunochromatographic strip testing is a rapid and non-invasive method of diagnosing kala-azar, which has good sensitivity and specificity and is well suited for use in field conditions.

Adolescent↗
PubMed1998

Treatment of antimony-unresponsive Indian visceral leishmaniasis with ultra-short courses of amphotericin-B-lipid complex.

High cost is the principal drawback of treating visceral leishmaniasis (VL; kala-azar) with any of the new lipid formulations of amphotericin B. The aim of the present study was to see if the costs of treatment with such drugs could be reduced by using ultra-short courses. Amphotericin-B-lipid complex (ABLC) was given to 77 Indian patients with antimony-unresponsive VL, either as a single infusion of 5 mg/kg (Group A) or two infusions, each of 5 mg/kg, given 5 days apart (Group B) or on consecutive days (Group C). Other than the anticipated higher fever and chills, treatment was well-tolerated. On day 19 after first infusion, 72 patients were considered apparent cures: 24 (89%) of the 27 in Group A; all 24 (100%) in Group B; and 24 (92%) of the 26 patients in Group C. Six months after treatment, 19 (70%) of 27 in Group A, 19 (79%) of 24 in Group B, and 21 (81%) of 26 in Group C were healthy, relapse-free and considered definitive cures. These cure rates were not statistically different. All 18 treatment failures (five initial non-responders and 13 relapses) were cured after treatment with a 5-day course of ABLC at a higher dose (10-15 mg/kg.day). In a related analysis of hospital plus drug costs for treating antimony-unresponsive VL, short-course ABLC (1-5 days) was compared with conventional amphotericin B (0.75-1.0 mg/kg on alternate days over 30-34 days). This analysis, which included the cost of re-treatment, identified one short-course ABLC regimen with an overall estimated expense which was only modestly higher than that of amphotericin B. Together, the present results provide further support for the use of ABLC in the management of VL patients who fail antimony therapy.

Adolescent↗
PubMed1998

Therapeutic effect of interferon-gamma gene transfer in experimental visceral leishmaniasis.

Interferon (IFN)-gamma, in both natural endogenous form and administered as exogenous protein, induces control over visceral Leishmania donovani in experimentally infected BALB/c mice. To further characterize the therapeutic role of IFN-gamma in host defense against intracellular L. donovani, the efficacy of IFN-gamma delivered by gene transfer was tested. One week after infection, normal and IFN-gamma gene-disrupted (GKO) BALB/c mice were injected with an IFN-gamma gene-bearing mammalian expression plasmid (pIFN). Plasmid-specific IFN-gamma transcripts were detected in liver and spleen. Whereas liver parasite burdens more than doubled in untreated and mock-treated normal and GKO mice during the subsequent 2 weeks, animals injected with pIFN had controlled visceral infection and reduced parasite burden. These results indicate that, in infected tissues, IFN-gamma delivered by gene transfer enhances control over disseminated intracellular infection.

Animals↗
PubMed1998

Splenic cytokine responses in Indian kala-azar before and after treatment.

Cytokine mRNA levels were measured in serial splenic aspirates from 27 patients with visceral leishmaniasis during monotherapy with interferon-gamma (IFN-gamma; n = 9), sodium antimony gluconate (SAG; n = 8), or amphotericin B lipid complex (ABLC; n = 10). At baseline, mRNA for IFN-gamma was detected in 18 (86%) of 21 patients, and mRNA for interleukin (IL)-10 and IL-4 was detected in 21 (100%) and 10 (48%) of 21 patients, respectively. With IFN-gamma treatment alone, levels of IFN-gamma mRNA decreased by day 10 and then returned to baseline levels; IL-10 mRNA levels were high throughout treatment. In the SAG and ABLC groups, levels of IFN-gamma and IL-10 mRNA decreased significantly. Polarized Th2 cell type responses do not appear to develop in Indian kala-azar; instead, there is an initial mixed Th1-Th2 cell picture. With successful treatment and resolution of infection, both components of the immune response appear to involute.

Adolescent↗
PubMed1998

A cluster of cases of severe cardiotoxicity among kala-azar patients treated with a high-osmolarity lot of sodium antimony gluconate.

In India, sodium antimony gluconate is the drug of choice for kala-azar. Due to increasing unresponsiveness to this drug in the current epidemic that began in the early 1970s, daily doses of 20 mg/kg/day for 30 days or more is recommended as opposed to the 10 mg/kg/day dose for 6-10 days used in the past. Of the 130-150 patients treated annually at our center with locally made sodium antimony gluconate, serious cardiotoxicity has occurred in less than 10%. During April 1995 at the University Hospital in Varanasi, we encountered life-threatening cardiotoxicity after 3-28 days of therapy in each of the eight patients being treated with a new lot of this drug made by a different manufacturer. Of the eight patients, six each developed congestive heart failure and/or prolongation of the corrected QT interval (QTc), and three died as a direct consequence of drug-induced toxicities. In three instances, the life-threatening complications occurred with a cumulative dose of less than 300 mg/kg. In patients with prolonged QTc, ventricular premature beats and ventricular tachycardia were recorded; in one patient, the ventricular tachycardia progressed to torsade de pointes, culminating in ventricular fibrillation and death. Since switching to different lots of this drug, we have not seen further clustering of dangerous cardiotoxicity. The antimony content of the implicated drug was comparable with that in lots from other manufacturers that did not show overt toxicity, but the osmolarity was approximately 300 mOsm/L higher. The simple technique of measuring of osmolarity may help identify inappropriately manufactured drug.

Adult↗
PubMed1997

Short-course, low-dose amphotericin B lipid complex therapy for visceral leishmaniasis unresponsive to antimony.

BACKGROUND: Visceral leishmaniasis (kala-azar) is a worldwide, disseminated intracellular protozoal infection for which prolonged, conventional therapy with pentavalent antimony has become increasingly less effective. OBJECTIVE: To determine the efficacy and minimal effective dose of short-course therapy with amphotericin B lipid complex in visceral leishmaniasis. DESIGN: A randomized, open-label study. SETTING: Inpatient kala-azar treatment unit in the state of Bihar in northeast India, where visceral leishmaniasis is endemic. PATIENTS: 60 patients with active infection who had not responded to or who had relapse after receiving conventional (> 30 days) treatment with pentavalent antimony. INTERVENTION: Intravenous amphotericin B lipid complex was given once daily for 5 consecutive days by 2-hour infusion. Patients were randomly assigned to receive 1, 2, or 3 mg/kg of body weight per day (total doses of 5, 10, or 15 mg/kg, respectively). MEASUREMENTS: Clinical and parasitologic responses (the latter were measured by parasite density score of the splenic aspirate) were determined 14 days after treatment. Definitive responses were assessed 6 months after treatment according to clinical outcomes and findings on examination of bone marrow aspirate. RESULTS: All 60 patients responded to 5 days of treatment. Fourteen days after therapy, all patients had parasite-free splenic aspirates and were considered to have an apparent clinical and parasitologic response. Six months after therapy, definitive responses were documented in 16 of 19 (84% [95% Cl, 60% to 97%]), 18 of 20 (90% [Cl, 68% to 99%]), and 21 of 21 (100% [Cl, 84% to 100%]) patients who received total doses of 5, 10, and 15 mg/kg, respectively. CONCLUSION: Short-course therapy with low-dose amphotericin B lipid complex is effective for visceral leishmaniasis and is an important therapeutic alternative in the management of this serious intracellular protozoal infection.

Adolescent↗
PubMed1997

Kala-azar comes to New York.

Visceral leishmaniasis (kala-azar) is a disseminated protozoal infection that occurs in areas of the world other than North America. In endemic regions, kala-azar is also an opportunistic infection associated with the acquired immunodeficiency syndrome. We report a case of acquired immunodeficiency syndrome-associated kala-azar acquired abroad that was first expressed in New York City. Human immunodeficiency virus-infected patients who have lived or traveled abroad may present in this country with unusual infections.

AIDS-Related Opportunistic Infections↗
PubMed1997

Intracellular antimicrobial activity in the absence of interferon-gamma: effect of interleukin-12 in experimental visceral leishmaniasis in interferon-gamma gene-disrupted mice.

Despite permitting uncontrolled intracellular visceral infection for 8 wk, interferon-gamma (IFN-gamma) gene knockout (GKO) mice infected with Leishmania donovani proceeded to reduce liver parasite burdens by 50% by week 12. This late-developing IFN-gamma-independent antileishmanial mechanism appeared to be dependent largely on endogenous tumor necrosis factor-alpha (TNF-alpha): L. donovani infection induced TNF-alpha mRNA expression in parasitized GKO livers and neutralization of TNF-alpha reversed control at week 12.7 d of treatment of infected GKO mice with interleukin-12 (IL-12) readily induced leishmanicidal activity and also partially restored the near-absent tissue granulomatous response, observations that for the first time expand the antimicrobial repertoire of IL-12 to include IFN-gamma-independent effects. The action of IL-12 against L. donovani was TNF-alpha dependent and required the activity of inducible nitric oxide synthase. These results point to the presence of an IFN-gamma-independent antimicrobial mechanism, mediated by TNF-alpha, which remains quiescent until activated late in the course of experimental visceral leishmaniasis. However, as judged by the effect of exogenous IL-12 this quiescent mechanism can readily be induced to rapidly yield enhanced intracellular antimicrobial activity.

Animals↗
PubMed1997

Behavior of visceral Leishmania donovani in an experimentally induced T helper cell 2 (Th2)-associated response model.

Although implicated in the clinical expression of human visceral leishmaniasis, a disease-exacerbating T helper cell 2 (Th2)-associated immune response involving interleukin-4 (IL-4) and/ or IL-10 is not readily detectable in experimental visceral infection. To overcome this obstacle to analyzing visceral Leishmania donovani in this relevant immunopathogenetic environment, we sought a model in which a Th2 response induces noncuring infection. Four initial approaches were tested primarily in BALB/c mice which control intracellular L. donovani via an IL-12- and interferon-gamma (IFN-gamma)-dependent Th1 mechanism: (a) modifying the cytokine milieu when the parasite is first encountered (treatment with exogenous IL-4 or anti-IL-12), (b) providing sustained endogenous exposure to a Th2 cytokine (infection of IL-4 transgenic mice), (c) increasing the parasite challenge inoculum, and (d) injecting heat-killed L. major promastigotes (HKLMP) to induce a cross-reactive Th2 response to live L. donovani. Only the last approach generated a functional Th2-type response that induced disease exacerbation accompanied by inhibition of tissue granuloma assembly. In HKLMP-primed BALB/c mice, prophylaxis with anti-IL-4, anti-IL-10, or exogenous IL-12 (but not IFN-gamma) readily restored resistance. In primed mice with established visceral infection, treatment with either IL-12 or IFN-gamma also successfully induced antileishmanial activity. The results in this model (a) suggest that rather than acting alone, IL-4 and IL-10 may act in concert to prevent acquisition of resistance to L. donovani, (b) reemphasize the capacity of IL-12 to reverse early Th2-related effects, and (c) demonstrate that Th1 cytokines (IL-12, IFN-gamma) have therapeutic action in an established systemic infection despite the presence of a disease-exacerbating Th2-type response.

Animals↗
PubMed1997

Endogenous interleukin-12 regulates acquired resistance in experimental visceral leishmaniasis.

Treatment with interleukin-12 (IL-12) induces leishmanicidal activity in experimental Leishmania donovani infection; therefore, BALB/c mice were injected with anti-IL-12 antibody to define the role of endogenous IL-12 in acquired resistance in this disseminated intracellular infection. Anti-IL-12 administration started 1 day after infection and given for 4 weeks abolished control of visceral parasite replication and in parallel suppressed endogenous interferon-gamma production and tissue granuloma assembly. Early (during week 1 only) and delayed treatment (during weeks 2-4 only) with anti-IL-12 also exacerbated visceral infection at week 4. These results point to a central role for endogenous IL-12 in acquired resistance to intracellular L. donovani and suggest that IL-12 is active in the cell-mediated immune response beyond the initial stage of host-parasite interaction.

Animals↗
PubMed1997

Response to interferon-gamma plus pentavalent antimony in Indian visceral leishmaniasis.

One hundred fifty-six previously untreated Indian patients with visceral leishmaniasis were treated with pentavalent antimony (Sb) alone for 30 days (group A), Sb plus interferon-gamma (IFN-gamma) for 30 days (group B), or Sb plus IFN-gamma for 15 days (group C). The purpose was to show that IFN-gamma would increase the response to 30 days of Sb treatment and that short-course (15 days) combination therapy was as effective as 30 days of Sb alone. Six months after treatment, 36% of group A, 49% of group B, and 42% of group C patients were designated as definitively cured. The success rates for long-term responses to Sb alone (36%) and Sb plus IFN-gamma (49%) were unexpectedly low, and responses in groups A, B, and C were not significantly different. These results suggest that the beneficial effects of adjunctive IFN-gamma in visceral leishmaniasis may be limited in regions where this disseminated intracellular infection shows high-level resistance to Sb.

Adolescent↗
PubMed1997

Circulating T helper 1 (Th1) cell- and Th2 cell-associated cytokines in Indian patients with visceral leishmaniasis.

Sera from 61 Indian patients with visceral leishmaniasis caused by infection with Leishmania donovani were tested for the presence of T helper 1 (Th1) cell-(interferon-gamma [IFN-gamma]) and Th2 cell-associated cytokines (interleukin-4 [IL-4] and IL-10). The IFN-gamma activity was detected in 53%. IL-4 in 84%, and IL-10 in 56% of patient samples. Sera from 10 healthy Indian controls showed detectable IFN-gamma in 90%. IL-4 in 10%, and IL-10 in 20%; corresponding percentages for sera from eight healthy American controls were 100%, 12%, and 0%, respectively. Quantitative data for the 61 patients compared with the 10 Indian controls indicated comparable mean levels of IFN-gamma, but three- and 13-fold increases in IL-10 and IL-4, respectively. Undetectable IFN-gamma activity, observed in 47% of patients, was associated with the presence IL-4 alone or in combination with IL-10 but not with IL-10 alone. In patients who had failed prior therapy (n = 29) compared with previously untreated patients (n = 32). IFN-gamma levels were 67% lower and IL-4 levels were two-fold higher, IL-10 activity was comparable. These results using peripheral blood support the presence of a suppressive Th2 cell-associated immune response in symptomatic Indian kala-azar and point to a possible role for IL-4.

Adult↗