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PubMed1993

Treatment of cryptosporidial diarrhea in an AIDS patient with paromomycin.

OBJECTIVE: To report a case of diarrhea caused by Cryptosporidium in an AIDS patients which was successfully treated with paromomycin. CASE SUMMARY: An AIDS patient with a 12-month history of cryptosporidial diarrhea unresponsive to other treatment measures was treated with paromomycin 500 mg q6h for 14 days. Before initiating therapy, the patient was experiencing, on average, 20 bowel movements per day and had lost more than 25 kg. After therapy was initiated, the number of bowel movements dropped to 1-2 per day and the patient began to gain weight. The diarrhea recurred when therapy was discontinued. After retreatment for 14 days with paromomycin 500 mg q6h, the diarrhea stopped. The patient has not had a recurrence of Cryptosporidium diarrhea, stool cultures remain negative for Cryptosporidium oocysts, and the patient has regained most of the weight. DISCUSSION: Literature concerning the use of paromomycin for the treatment of cryptosporidiosis is discussed. A treatment algorithm for the management of cryptosporidiosis in AIDS patients is presented. CONCLUSIONS: We believe that we have presented a clear example of a case in which paromomycin was effective in treating and eradicating intestinal cryptosporidiosis in an AIDS patient. Paromomycin is the most effective agent available to date for the treatment of this devastating complication of AIDS.

AIDS-Related Opportunistic Infections↗
PubMed1995

Paromomycin-associated pancreatitis in HIV-related cryptosporidiosis.

OBJECTIVE: To report a case of pancreatitis related to paromomycin administration. CASE SUMMARY: A 39-year-old man with AIDS developed pancreatitis concurrent with successful treatment of intestinal cryptosporidiosis with paromomycin. The hyperamylasemia resolved with discontinuation of the agent and recurred when paromomycin treatment was reinstituted. DISCUSSION: To our knowledge, this is the first reported case of pancreatitis believed to be induced by paromomycin. Although pancreatitis in HIV-infected patients has multiple causes, the nature of this case suggests the involvement of paromomycin. The mechanism of action is unclear. CONCLUSIONS: Pancreatitis should be considered in the differential diagnosis of abdominal pain in patients who are treated with paromomycin.

AIDS-Related Opportunistic Infections↗
PubMed1983

Effect of long-term administration of paromomycin sulfate on the level of serum albumin and gamma-globulin in human cirrhosis.

The efficacy of administration of oral paromomycin sulfate on serum albumin and gamma-globulin levels was studied in cirrhotic patients. After an observation period of 3 months, paromomycin sulfate at 2.0 g per day or a placebo was administered for 6 months, and changes in serum albumin and in gamma-globulin levels were examined every three months. Out of 16 cirrhotic patients treated with paromomycin, 11 (68.8%) showed significant increases in serum albumin compared with one out of 16 in the placebo group. Concerning gamma-globulin, seven (43.8%) patients in the paromomycin group showed significant decreases compared with one in the placebo group. In addition, among the 11 cirrhotics whose endotoxemia decreased after paromomycin administration, eight (72.7%) showed significant increases in albumin level. It was suggested that paromomycin improves the serum albumin and gamma-globulin levels in cirrhosis through the alleviation of endotoxemia caused by intestinal bacteria.

Clinical Trials as Topic↗
PubMed1983

[Efficacy of paromomycin sulfate against human cestodiasis and its pharmacological action on tapeworm in vitro].

Recently, it has been reported that paromomycin sulfate has marked anthelmintic efficacy against tapeworm infections in man. In the present study this drug was used in the treatment of 14 cases of diphyllobothriasis latum and 1 case of taeniasis saginata. Also, the actions of paromomycin sulfate on Diphyllobothrium ditremum and D. erinacei were examined pharmacologically using Magnus apparatus and biochemical methods. The results obtained were as follows. For the treatment, a total of 50 mg/kg of paromomycin sulfate divided into 2 doses was given orally at intervals of 30 minutes. Two hours after medication, 20 g of magnesium sulfate dissolved in 200--300 ml of water was given as purgative. One or 2 worms were found in the stools of 11 cases with D. latum and 1 case with T. saginata within 24 hours after medication, but scolex was found in only 2 of them. All cases were negative for the eggs or segments in stool examinations at 1 and 3 months after treatment. Except 1 case complained mild and transient vomiting no side effects were noticed. All cases showed no abnormality in blood examination, liver function test and urinalysis. Both of the proglottids of D. ditremum and D. erinacei showed muscle relaxation in Tyrode solution containing 10(-4) g/ml of paromomycin sulfate. In D. ditremum the recovery of muscle tonus was observed within 10--15 minutes after affection of this drug, while the persistence of muscle relaxation was seen in D. erinacei. The activity of phosphoglucose isomerase was slightly inhibited by 10(-3) M paromomycin sulfate while those of hexokinase, phosphofructokinase and glucose-6-phosphate dehydrogenase were not inhibited. In phosphoenolpyruvate-succinate pathway, the activity of fumarate reductase was slightly inhibited 10(-3) M paromomycin sulfate while those of phosphoenolpyruvate carboxykinase and malate dehydrogenase were not inhibited.

Adolescent↗
PubMed1983

[The effect of paromomycin sulfate on Diphyllobothrium latum].

Nine vital tapeworms were expelled from 7 patients with diphyllobothriasis latum by the modified Damaso De Rivas' method. Seven worms of them placed in 1% and 5% paromomycin solution (37 degrees C, pH 6.8--6.9) and 2 were in physiological saline at 37 degrees C as controls. In both 1% and 5% solution, the movement of worms stopped completely within 15 minutes. When they were taken out from the solution and washed thoroughly with physiological saline solution, they did not move any longer and died soon. As for the controls, they were moving with animation in physiological saline at 37 degrees C even after 60 minutes. Pathohistologically (H.E. stain), the scolex was seriously affected down to the immature proglottid; degeneration and desquamation of the villi and cuticle with somatic cells exposed and edematous swelling of the whole body. Somatic cells had degenerative necrosis, plasmatomy and disorder in the disposition of the circular muscle and longitudinal muscle were marked. Scanning electronmicroscopy revealed that the worms treated with paromomycin had the scolex remarkably impaired and destroyed the villous epithelial layer and cuticle of the immature proglottid adjacent to the scolex desquamated exposing somatic cells regardless of the duration of exposure to and the concentration of paromomycin, while in the controls, the scolex was normal and the worm surface was closely covered with normal villi. Aminoglycoside antibiotics are known to have neurotoxic effect in general. It seems to be related to this neurotoxicity that paromomycin solution stopped the movement of worms. The changes occurring in the tapeworms were irreversible and the worms died soon. It is suggested that when patients with diphyllobothriasis latum are administered with paromomycin, the alterations of the worms induced by paromomycin are accelerated by potent human digestive juice.

Animals↗
PubMed1997

Effect of treatment with paromomycin on endotoxemia in patients with alcoholic liver disease--a double-blind, placebo-controlled trial.

The results of experimental and clinical studies support the hypothesis that gut-derived endotoxins might be of relevance for the development and course of alcoholic liver disease. The aim of this study was to test the effect of a nonabsorbable, broad-spectrum antibiotic on endotoxemia in patients with alcoholic liver disease. Fifty patients with alcoholic liver disease (27 with cirrhosis, 23 without cirrhosis) were randomly assigned to receive either paromomycin sulfate (3 x 1 g/day) or placebo in a double-blind fashion for at least 3 weeks, and if possible 4 weeks. Endotoxin concentration, liver function tests, and other laboratory parameters were determined in weekly intervals. Endotoxin concentration was also determined in 15 healthy controls. Groups receiving paromomycin or placebo were similar for clinical and biological items collected initially. Mean initial endotoxin concentrations were significantly elevated in both groups (mean +/- SEM; paromomycin, 16.7 +/- 5.3 pg/ml; placebo, 17.5 +/- 6.9 pg/ml; healthy controls, 2.3 +/- 0.4 pg/ml). Although the mean endotoxin concentration was lower in the verum group after 1 week (paromomycin, 8.0 +/- 1.9 pg/ml; placebo, 14.6 +/- 3.5 pg/ml; p > 0.05), paromomycin treatment had no significant effect on endotoxin concentration or liver function tests during the 4-week period. The beneficial effect of paromomycin treatment on endotoxemia in cirrhotics reported in earlier studies could not be reproduced under the conditions of this trial in patients with alcoholic liver disease.

Adult↗
PubMed2003

Treatment of cutaneous leishmaniasis with either topical paromomycin or intralesional meglumine antimoniate.

Ninety-six patients with a clinical and parasitological diagnosis of cutaneous leishmaniasis were recruited to a comparative randomized clinical trial evaluating the efficacy of topical paromomycin vs. weekly intralesional injections of meglumine antimoniate. The patients were randomly divided into two treatment groups: one group was treated with topical paromomycin ointment and the other with intralesional meglumine antimoniate. Treatment was continued in both groups until complete recovery occurred (defined as healing in less than 2 months with no residual scar or relapse for up to 1 year post treatment). Treatment failure was defined as an increase in the number and size of pre-existing lesions or untoward side-effects. The maximum treatment period was 3 months. The patients were followed up for 1 year. The results showed that intralesional meglumine antimoniate led to 41.7% complete recovery, However, topical paromomycin gave a lower cure rate of 16.6% (P < 0.05). Treatment failure was observed in 39.7% of the group receiving intralesional meglumine and in 72.9% of those on topical paromomycin (P < 0.05). This study indicates that intralesional meglumine antimoniate is superior to topical paromomycin in the treatment of cutaneous leishmaniasis.

Administration, Topical↗
PubMed2005

Complete thermodynamic characterization of the multiple protonation equilibria of the aminoglycoside antibiotic paromomycin: a calorimetric and natural abundance 15N NMR study.

The binding of aminoglycoside antibiotics to a broad range of macromolecular targets is coupled to protonation of one or more of the amino groups that typify this class of drugs. Determining how and to what extent this linkage influences the energetics of the aminoglycoside-macromolecule binding reaction requires a detailed understanding of the thermodynamics associated with the protonation equilibria of the aminoglycoside amino groups. In recognition of this need, a calorimetric- and NMR-based approach for obtaining the requisite thermodynamic information is presented using paromomycin as the model aminoglycoside. Temperature- and pH-dependent 15N NMR studies provide pK(a) values for the five paromomycin amino groups, as well as the temperature dependence of these pK(a) values. These studies also indicate that the observed pK(a) values associated with the free base form of paromomycin are lower in magnitude than the corresponding values associated with the sulfate salt form of the drug. This difference in pK(a) is due to drug interactions with the sulfate counterions at the high drug concentrations (> or = 812 mM) used in the 15N NMR studies. Isothermal titration calorimetry studies conducted at drug concentrations < or = 45 microM reveal that the extent of paromomycin protonation linked to the binding of the drug to its pharmacologically relevant target, the 16 S rRNA A-site, is consistent with the pK(a) values of the free base and not the sulfate salt form of the drug. Temperature- and pH-dependent isothermal titration calorimetry studies yield exothermic enthalpy changes (deltaH) for protonation of the five paromomycin amino groups, as well as positive heat capacity changes (deltaC(p)) for three of the five amino groups. Regarded as a whole, the results presented here represent an important first step toward establishing a thermodynamic database that can be used to predict how aminoglycoside-macromolecule binding energetics will be influenced by conditions such as temperature, pH, and ionic strength. Such a predictive capability is a critical component of any drug design strategy.

Aminoglycosides↗
PubMed1999

Successful topical treatment of murine cutaneous leishmaniasis with a combination of paromomycin (Aminosidine) and gentamicin.

Cutaneous leishmaniasis is presently treated with 20 days of parenteral therapy with a frequently toxic drug (antimony). Topical formulations of paromomycin (15%) plus methylbenzethonium chloride (MBCL, 12%) or plus urea (10%) in soft white paraffin have been tested for Old and New World disease in humans. We compared the efficacy of a new topical formulation, WR 279,396 (paromomycin [15%] plus gentamicin [0.5%]) to the clinical formulations in the treatment of cutaneous disease in BALB/c mice. Sixty-day-old lesions were treated twice a day for 10 days, and the response to therapy was determined over a further 70 days. For ulcers due to Leishmania major or to Leishmania mexicana, 100% of lesions in the WR 279,396 group healed by day 20 after therapy and did not relapse by day 70; 83% of lesions healed without relapse in the paromomycin-MBCL group. In the paromomycin-urea group, 100% of L. major lesions healed by day 30 but 30% relapsed. For ulcers due to Leishmania panamensis or Leishmania amazonensis, all lesions treated with WR 279,396 healed and did not relapse; < 50% of lesions treated with paromomycin-MBCL healed by day 30, and all lesions relapsed by day 70. In addition to being active, WR 279,396 was not toxic in this model and appears to have a cosmetic effect (promoting hair growth, healing, and limiting the size of the scar).

Administration, Topical↗
PubMed1981

[Comparative study of serum levels and urinary excretion following oral administration of paromomycin and neomycin (author's transl)].

In a comparative study absorption and elimination characteristics of p.o. administered paromomycin and neomycin were investigated in healthy volunteers and patients with liver cirrhosis and/or portocaval shunt. Serum and urine concentrations were determined by means of the diffusion test. 1. In a cross-over study 6 volunteers were each administered single p.o. doses of 14.28 g paromomycin sulfate (= 10 g free base = 1.6 X 10(-2) mol) and 16 g neomycin sulfate (= 10.65 g free base = 1.7 X 10(-2) mol). Following these virtually equimolar doses AUC values of neomycin were 2.5 times as high as those of paromomycin (p less than 0.01). Paromomycin serum level time courses could be described by an open one-compartment model with a mean half-life of 2.6 h (harmon. mean). Mean computed maximum levels of 3.6 microgram/ml appeared on an average of 1.9 h after administration. After 32 h the mean recovery in urine was 0.2%. 5 volunteers showed a similar behavior with a mean excretion of 0.1%, whereas one person excreted 0.8% in urine. The time course of neomycin was evaluated according to an open two-compartment model with a distribution half-life of 1.5 h and a terminal half-life of 9 h (harmon. means). Mean computed maximum levels of 5.1 microgram/ml appeared on an average of 2.6 h after administration. The mean lag time was 1.3 h. 32 h after administration 0.3% of the dose were detected in urine. 2. Patients with cirrhosis and/or portocaval shunt were treated with 8 capsules/d of either 357.1 mg paromomycin sulfate or 250 mg neomycinsulfate each over a period of 7 days. Despite the lower dose of neomycin comparable serum levels of both aminoglycosides were observed. This result can be explained by a lower elimination rate and a higher extent of accumulation of neomycin. Mean amounts excreted in the urine of the 7th day were 0.1% for paromycin and 0.2% for neomycin.

Adult↗
PubMed1995

Therapeutic efficacy of paromomycin in immunosuppressed adult mice infected with Cryptosporidium parvum.

The intent of this study was to evaluate the therapeutic efficacy of paromomycin in immunosuppressed adult C57BL/6N mice infected with Cryptosporidium parvum. Seven groups of 10 mice/group were used. Groups 1, 2, and 7 served as normal, toxicity, and placebo controls, respectively. Groups 2-7 were immunosuppressed with dexamethasone phosphate administered ad libitum in drinking water. Groups 3-7 were infected with C. parvum on day 7 postimmunosuppression. Groups 3-6 were treated by administering paromomycin per os for 10 consecutive days, beginning on day 10 postinfection, at dosage levels of 0.25, 0.5, 1, and 2 g/kg/day, respectively. Paromomycin was judged to be nontoxic at the dosage levels used. Groups 1 and 2 remained uninfected while groups 3-7 began shedding oocysts by day 3 postinfection. Paromomycin was therapeutically effective against C. parvum at 1 and 2 g/kg/day as determined by significant reductions in fecal oocyst shedding (P < 0.01), parasite colonization (P < 0.05), and villus atrophy (P < 0.05) in the ilea and terminal ilea of infected mice. We conclude that paromomycin may be useful in the treatment and palliation of cryptosporidiosis.

Animals↗
PubMed1981

Ribosomal suppressors and antisuppressors in Podospora anserina: altered susceptibility to paromomycin and relationships between genetic and phenotypic suppression.

Informational suppressors and antisuppressors have been previously isolated in Podospora anserina, and their properties suggest that they could be ribosomal mutants involved in the control of translational fidelity. In this paper we present results concerning relationships between these mutants and paromomycin, an aminoglycoside antibiotic known to stimulate translational errors. The mutants were found to manifest an altered growth sensitivity to this drug as compared with the wild-type strain: Most of the suppressors were more sensitive and, in contrast, most of the antisuppressors were more resistant to paromomycin. Moreover, phenotypic suppression of an auxotrophic mutation by paromomycin was observed only if a suppressor and an antisuppressor had been introduced in the strain. These results suggest that ambiguity levels could be altered in the suppressor and antisuppressor strains. In addition, paromomycin was shown to abolish sporulation, which suggests relationships between mistranslation and a step of cellular differentiation.

Ascomycota↗
PubMed2006

Synthesis of paromomycin derivatives modified at C(5'') to selectively target bacterial rRNA.

The furanosyl moiety (ring III) of C(6')-deoxyparomomycin and paromomycin was modified in search of aminoglycoside antibiotics with altered selectivity. The key intermediates were the N-Boc-protected derivative of C(6')-deoxyparomomycin and the benzylidene-protected paromomycin. Their H(2)C(5'')-OH group was oxidised with trichlorocyanuric acid or [bis(acetoxy)iodo]benzene in the presence of catalytic amounts of TEMPO to yield the corresponding aldehydes and acids, which were transformed into the protected alkoxy imines, amides and the amine. Standard deprotection gave the title compounds derived from C(6')-deoxyparomomycin and derived from paromomycin that proved less active than paromomycin and its C(6')-deoxy analogue.

Mycobacterium smegmatis↗
PubMed2002

Footprinting and circular dichroism studies on paromomycin binding to the packaging region of human immunodeficiency virus type-1.

We have studied the interaction of the aminoglycoside drug, paromomycin, with a 171-mer from the packaging region of HIV-1 (psi-RNA), using quantitative footprinting and circular dichroism spectroscopy. The footprinting autoradiographic data were obtained by cutting end-labeled RNA with RNase I or RNase T1 in the presence of varying paromomycin concentrations. Scanning the autoradiograms produced footprinting plots showing cleavage intensities for specific sites on the psi-RNA as functions of drug concentration. Footprinting plots showing binding were analyzed using a two-state model to give apparent binding constants for specific sites of the psi-RNA. These plots show that the highest-affinity paromomycin binding site involves nucleotides near bulges in the main stem and SL-1, and other nucleotides in SL-4 of the psi-RNA. RNase I gives an apparent value of K for this drug site of approximately 1.7 x 10(5) M(-1) while RNase T1 reports a value of K of approximately 8 x 10(4) M(-1) (10 mM Tris HCl, pH 7). Footprinting shows that loading the highest affinity site with paromomycin causes structural changes in the single-stranded linker regions, between the stem-loops and main stem and the loops of SL-1 and SL-3. Drug-induced structural changes also affect the intensity of the 208 nm band in the circular dichroism spectrum of the psi-RNA. Fitting the changes in CD band intensity to a two-state model yielded a binding constant for the highest-affinity drug site of 6 x 10(6) M(-1). Thus, the binding constants from footprinting are lower than those obtained for the highest-affinity site from the circular dichroism spectrum, and lower than those earlier obtained using absorption spectroscopy (Sullivan, J. M.; Goodisman, J.; Dabrowiak, J. C., Bioorg. Med. Chem. Lett. 2002, 12, 615). The discrepancy may be due to competitive binding between drug and cleavage agent in the footprinting experiments, but other explanations are discussed. In addition to revealing sites of binding and regions of drug-induced structural change, footprinting showed that the loop regions of SL-1, SL-3 and SL-4 are exposed in the RNA, whereas the linker region between SL-1 and SL-2 is 'buried' and not accessible to cutting by RNase I or RNase T1.

Algorithms↗
PubMed1998

Development and characterization of paromomycin-resistant Leishmania donovani promastigotes.

Paromomycin is an antileishmanial chemotherapeutic agent. Leishmania donovani promastigotes resistant to 800 microM of paromomycin were selected by increasing drug pressure and cloned. These promastigotes did not acquire multidrug resistance. Paromomycin resistance was stable in the absence of the drug in the culture. It remained stable also in amastigotes isolated after a passage in mice. Furthermore the resistant parasites were still infective to macrophages in vitro and for mice in vivo. A sensitive method to detect and to quantify intracellular paromomycin by HPLC was developed and allowed to show that the main mechanism of resistance seems to be due to decreased drug uptake probably as a consequence of altered membrane composition.

Animals↗
PubMed1998

Difficult-to-treat trichomoniasis: results with paromomycin cream.

Vaginal trichomoniasis poses a difficult therapeutic challenge when metronidazole is ineffective or contraindicated. We conducted a retrospective study of 6.25% paromomycin cream in the treatment of nine women referred with cases of vaginal trichomoniasis where metronidazole resistance or allergy was present. Results obtained immediately and 1 month after treatment were reviewed. The median age of the patients was 46 years; four women were nulliparous. The median symptom duration was 1 year. Five women were allergic to metronidazole. In four cases, resistance to high doses of metronidazole was demonstrated. Smears or cultures were positive immediately after treatment for three patients; a fourth relapsed 2 weeks later. Of these patients for whom treatment failed, one was cured with a 3-week course of paromomycin cream, and another was successfully treated with paromomycin cream and oral tinidazole. Three patients developed vaginal ulcerations that resolved spontaneously. Adverse effects may be a result of local formulation. Paromomycin cream was useful for treatment of cases of trichomonas infection where metronidazole resistance or allergy was encountered.

Adult↗
PubMed1994

Paromomycin: an effective treatment for cryptosporidial diarrhea in patients with AIDS.

Cryptosporidiosis is a common cause of diarrhea in patients with AIDS but remains one of the most challenging AIDS-related conditions to treat. We therefore carried out an open, uncontrolled, prospective study to evaluate the efficacy of oral paromomycin for the treatment of chronic diarrhea due to Cryptosporidium in 24 successive patients infected with human immunodeficiency virus. Twenty-two of the 24 patients responded clinically, with complete remission occurring in 18 cases and marked reduction of the diarrhea occurring in four. Clearance of cryptosporidia from stools and/or intestinal biopsy specimens occurred within 2-4 weeks. Furthermore, all 18 patients who achieved complete remission gained weight. Ten patients relapsed either during administration of maintenance therapy or after discontinuation of treatment, but diarrhea resolved again after increasing or restarting paromomycin therapy in all but two. Paromomycin appeared to be an active and well-tolerated treatment for cryptosporidiosis in patients with AIDS. Efficacy is dose-related, and continuous maintenance therapy is required to prevent relapses. These data suggest that paromomycin might be given as first-line therapy in AIDS-related cryptosporidiosis, but this should be confirmed by the findings of a controlled, randomized trial.

AIDS-Related Opportunistic Infections↗
PubMed1992

Paromomycin inhibits Cryptosporidium infection of a human enterocyte cell line.

Cryptosporidium parvum is a protozoan parasite that causes severe enteritis in patients with AIDS for which there is no effective therapy. Paromomycin is a nonabsorbable aminoglycoside that is effective in the treatment of other intestinal protozoa. The ability of paromomycin to inhibit C. parvum infection of a differentiated human enterocyte cell line was evaluated in vitro. Paromomycin concentrations ranging from 50 to 5000 micrograms/ml inhibited infection at 24 h in a dose-dependent fashion. Concentrations greater than 1000 micrograms/ml, which are theoretically achievable in the bowel lumen, inhibited infection by greater than 85% (P less than .001). Prospective clinical trials of paromomycin for the treatment of cryptosporidiosis in patients with AIDS are warranted.

Animals↗