Machine learning-based predictive models for identifying high active compounds against HIV-1 integrase.

HIV-integrase is an important drug target because it catalyzes chromosomal integration of proviral DNA towards establishing latent infection. Computer-aided drug design has immensely contributed to identifying and developing novel antiviral drugs. We have developed various machine learning-based predictive models for identifying high activity compounds against HIV-integrase. Multiclass models were built using support vector machine with reasonable accuracy on the test and evaluation sets. The developed models were evaluated by rigorous validation approaches and the best features were selected by Boruta method. As compared to the model developed from all descriptors set, a slight improvement was observed among the selected descriptors. Validated models were further used for virtual screening of potential compounds from ChemBridge library. Of the six high active compounds predicted from selected models, compounds 9103124, 6642917 and 9082952 showed the most reasonable binding-affinity and stable-interaction with HIV-integrase active-site residues Asp64, Glu152 and Asn155. This was in agreement with previous reports on the essentiality of these residues against a wide range of inhibitors. We therefore highlight the rigorosity of validated classification models for accurate prediction and ranking of high active lead drugs against HIV-integrase.

A prospective randomized, comparative, open-label trial of the safety and efficacy of paromomycin (aminosidine) plus sodium stibogluconate versus sodium stibogluconate alone for the treatment of visceral leishmaniasis.

Response to treatment with organic pentavalent antimonials, the standard first-line treatment for visceral leishmaniasis (VL), has been decreasing since their introduction into India. Combining sodium stibogluconate (SB) with paromomycin (PM) may be an efficient alternative to single-agent therapy. This trial was designed to assess the safety and efficacy of PM 12 or 18 mg/kg daily plus SB 20 mg/kg daily for 21 days compared to SB alone for 30 days. One hundred and fifty patients were randomly assigned in 1996 to 1 of the 3 treatments and followed-up for 180 days. At the end of treatment, 49 of 52 patients receiving PM12 + SB, 46 of 48 receiving PM18 + SB, and 27 of 49 patients receiving SB alone, were cured. During follow-up there was 1 relapse in each of the treatment groups, giving final cure rates of 48 of 52 (92.3%) for PM12 + SB, 45 of 48 (93.8%) for PM18 + SB, and 26 of 49 (53.1%) for SB. PM plus SB for 21 days at either 12 or 18 mg/kg daily was significantly more effective than SB alone for 30 days (chi 2 P < 0.001). One patient (SB alone) had experienced a serious adverse event: cardiotoxicity at day 8 (myocarditis and ECG changes) which caused withdrawal from the study. Only 19 of 100 patients enrolled in the PM treatment arms had a complete audiogram series conducted thus making it difficult to assess oto-toxicity. PM 12 or 18 mg/kg daily plus a standard dose of SB for 21 days was statistically more effective than SB in producing a final cure for patients with VL in Bihar, India.

Do the diminishing efficacy and increasing toxicity of sodium stibogluconate in the treatment of visceral leishmaniasis in Bihar, India, justify its continued use as a first-line drug? An observational study of 80 cases.

Eighty parasitologically confirmed cases of visceral leishmaniasis (kala-azar) in Bihar, India, were treated daily with 20 mg sodium stibogluconate/kg for 30 days, to assess the current efficacy and toxicity of this 30-day regimen. Clinical and parasitological cure was obtained in 48 (60%) of the patients. However, 26 (33%) patients did not respond to the first course of treatment (primary unresponsiveness), two relapsed after initial clinical and parasitological cure, and two were withdrawn from the study (one on day 6 of treatment because of cardiotoxicity in the form of supraventricular tachycardia and the other on day 24 because of severe loss of appetite). All 30 patients who were not entirely cured with sodium stibogluconate were successfully treated with amphotericin B. Electrocardiographic changes occurred in many of the patients as the result of treatment with sodium stibogluconate. Diminution in the height of the T wave was seen in 32 (40%), inversion of the T wave (Minnesota code 5-1, 5-2) in seven (9%), elevation of the ST segment (Minnesota code 4-1) in three (4%), prolonged QT interval (compared with baseline findings) in six (8%), and diminution in the height of the P, R and T waves in two (3%). Cardiac arrhythmia occurred in five patients (6%), supraventricular arrhythmia (coarse atrial fibrillation) occurred in one patient and ventricular tachycardia, ventricular fibrillation, torsade de pointes and multifocal ventricular ectopics occurred in the four patients (5%) who died of cardiotoxicity. Minor side-effects, such as pain at the site of injection (two cases), mild diminution in appetite (12 cases), metallic taste in mouth (six cases), and joint pain (two cases), were also observed. It was concluded that the efficacy of sodium stibogluconate in the study area has declined over the years and that its toxicity has increased. A more efficacious, safer and cheaper, alternative drug is required as the first line of treatment of kala-azar.

Pachydermoperiostosis in childhood.

We report a family with pachydermoperiostosis (idiopathic hypertrophic osteoarthropathy) spanning four generations with 10 affected individuals, four of whom are children although pachydermoperiostosis is rare in childhood. In this family, with intermarriage, the inheritance is autosomal recessive and it is possible that there are individuals who are homozygous for the pachydermoperiostosis gene. These individuals do not appear to be more severely affected, although one of them had a cleft palate and congenital heart defect which may be a manifestation of being homozygous.

Comparison of three treatment regimens with liposomal amphotericin B (AmBisome) for visceral leishmaniasis in India: a randomized dose-finding study.

The efficacy and safety of 3 regimens of liposomal amphotericin B (AmBisome) in the treatment of Indian visceral leishmaniasis were compared in a prospective open randomized trial. Thirty parasitologically confirmed patients were randomly divided into 3 equal treatment groups; group 1 received AmBisome 2mg/kg on days 1, 2, 3, 4, 5, 6, and 10 (total dose 14 mg/kg); group 2 received AmBisome 2 mg/kg on days 1, 2, 3, 4, and 10 (total dose 10 mg/kg); group 3 received the same dosage on 1, 5 and 10 (total dose 6 mg/kg). Clinical cure resulted in all patients by day 24. Haemoglobin, white blood cell count, body weight and serum albumin level improved on day 24 and became normal by day 180. No patient relapsed within 12 months of follow-up. Side effects were minimal. One patient in group 2 died after 2 months from an unrelated disease. Liposomal amphotericin B is a promising new drug which is highly efficacious in the treatment of Indian kala-azar and produces minimal toxicity.

Comparison of regimens of amphotericin B deoxycholate in kala-azar.

A total of 288 parasitologically proved patients of kala-azar were randomly allocated to three treatment groups. Patients in groups A, B and C received amphotericin B (AMB) in a dose of 1 mg/kg body weight (bw)/day, 0.75 mg/kg bw/day and 0.5 mg/kg bw/day for 20 days respectively. Apparent cure (afebrile at the end of therapy) occurred in all patients and parasitological cure in 96 (100%), 92 (96%) and 84 (88%) patients respectively in groups A, B and C. Ultimate cure (no relapse in six months of follow up) occurred in 95 (99%), 87 (91%) and 79 (82%) patients in groups A, B and C respectively. The difference between the ultimate cure in the three groups was significant (P < 0.05). The incidence of adverse events (rise in serum creatinine and fall in serum potassium, loss of appetite and shivering, rigor and fever during infusion indicative of renal, GIT and infusion related toxicities respectively) was similar in the three groups. This study showed that amphotericin B should be given at a dosage of 1 mg/kg bw/day for 20 days for Indian kala-azar patients to minimise relapses and prevent development of drug unresponsiveness.

Two-hour versus six-hour administration of amphotericin B in the treatment of kala-azar.

In a randomised study, 50 parasitologically confirmed cases of kala-azar were allocated to two treatment groups: group A received amphotericin B in 5% glucose infusion for 6 h and group B for 2 h. Amphotericin B was given at an initial dosage of 0.05 mg/kg body weight, increasing to 1 mg/kg body weight on day 5, and this dose was given daily until patients had received a total of 20 mg/kg body weight. Toxicities like rise in serum creatinine, fall in serum potassium levels and diminution in appetite were no different in the two groups. There was no difference in clinical, parasitological and ultimate cures between the two groups. Man-hours spent in treating patients in the 2-h infusion group were one-third of the time with the 6-h infusion group. It was concluded that 2-h infusion of amphotericin B caused fewer infusion-related toxicities (shivering and fever) and saved time spent in treating patients; hence it should be recommended for use.

Are incremental doses of amphotericin B required for the treatment of visceral leishmaniasis?

One-hundred-and-twenty visceral leishmaniasis patients, all with demonstrable splenic amastigotes after treatment with sodium stibogluconate and pentamidine, were treated with amphotericin B. The patients were allocated into two equal groups matched by age and sex. Patients in one group received amphotericin B in the traditional incremental dose regimen, i.e. 0.05, 0.10, 0.25, 0.50 and 1.0 mg/kg body weight on days 1, 2, 3, 4, and > 4, respectively. Patients in the other group received amphotericin B at a constant 1 mg/kg bodyweight per day from day 1. Each of the 120 patients received a total dose of 20 mg/kg bodyweight. By the end of treatment the incidence of infusion-related toxicities, such as rigor and fever, and of renal toxicities, such as elevated serum creatinine and low serum potassium, was the same in both groups (P > 0.05). The two treatment regimens were also equally effective; every patient was cured and none relapsed within 6 months' follow-up. It is therefore recommended that amphotericin B be given as the full optimal dose (1 mg/kg) from day 1. There seems no advantage in the incremental regimen; not only does it 'waste' 4 days before the optimal dose is reached but it is more expensive and may encourage the development of drug resistance.

Daily versus alternate-day regimen of amphotericin B in the treatment of kala-azar: a randomized comparison.

Using a randomized study, we compared a daily and an alternate-day regimen of amphotericin B for the treatment of kala-azar, with respect to efficacy, adverse reactions, cost-effectiveness, and tolerance. The study subjects were 80 kala-azar patients, drawn from the first four decades of life and matched by age, sex, and parasite load. The patients were randomly allocated to treatment groups A and B (40 patients per group). Patients in group A received a daily regimen of amphotericin B, starting with an escalating dose of 0.05 mg/kg body weight per day until a daily dose of 1 mg/kg was reached; the latter dose was then given daily till a total dose of 20 mg/kg body weight had been administered. The patients in group B also started with an escalating dose of 0.05 mg/kg but when 1 mg/kg was reached the drug was given on alternate days. All 80 patients using the two treatment regimens were cured, no patient relapsed in either group in 6 months of follow-up, and their bone-marrow aspirates were free of amastigotes. Treatment of kala-azar patients with the daily regimen of amphotericin B at a dose 1 mg/kg body weight was as effective, not more toxic, equally well tolerated, and much more cost-effective than the alternate-day regimen and should be adopted for treatment of this condition.

The treatment of kala-azar during pregnancy.

BACKGROUND: Kala-azar in pregnant women is difficult to treat because for them the two commonly used drugs, sodium stibogluconate and pentamidine, are not considered safe. We assessed the effect of amphotericin B on pregnancy, on the foetus and kala-azar. METHODS: Five pregnant women were administered amphotericin B at a dose of 1 mg/kg body weight daily starting with 0.5 mg/kg body weight till a total dose of 20 mg/kg body weight was given. The progress of pregnancy was monitored ultrasonographically and the mothers and children were followed for six months. RESULTS: All the 5 women were cured of the disease and there was no harmful effect on the children. CONCLUSION: Amphotericin B cures kala-azar during pregnancy with no harmful effects on the foetus.

Evaluation of amphotericin B as a first line drug in comparison to sodium stibogluconate in the treatment of fresh cases of kala-azar.

A total of 150 patients of kala-azar matched for age and sex and parasitologically proved were randomly allocated to two equal treatment groups. Patients in one group received amphotericin B(AMB) in a dose of 1 mg/kg body weight (BW) on alternate days starting with 0.05 mg/kg/bw on first day with daily increments, till a total dose of 20 mg/kg/bw was given; the patients in the second group received sodium stibogluconate (SAG) in the dose of 20 mg/kg/bw, im daily for 30 days. The efficacy, safety and cost-effectiveness of the two drugs were compared. Apparent cure (afebrile at the end of therapy) in 75 (100%) and 69 (92%) patients and ultimate cure (no relapse in six months of follow up) in 75 (100%) and 60 (80%) patients occurred in the AMB and SAG groups respectively. The difference between the ultimate cure in the two groups was significant (P < 0.001). Six (8%) and 9(12%) patients of SAG group showed primary (with no response to SAG during treatment) and secondary unresponsiveness (with no response to SAG after relapse) respectively and they were cured with amphotericin B.(ABSTRACT TRUNCATED AT 250 WORDS)

Amphotericin B in resistant kala-azar in Bihar.

BACKGROUND: During the recent epidemic of kala-azar in Bihar, we identified a group of patients who were unresponsive to the two commonly used drugs--sodium stibogluconate and pentamidine. We evaluated the use of amphotericin B in these patients because it has been shown to be active in experimental animals against amastigotes and promastigotes, it has been found to be useful in South American patients and is now recommended by the World Health Organization as a second line drug. METHODS: We selected 300 patients who were unresponsive to sodium stibogluconate and pentamidine (out of 500 patients with kala-azar confirmed by demonstration of Leishmania donovani bodies in their splenic aspirates). Amphotericin B was given in a dose of 1 mg/kg body weight on alternate days starting with 0.05 mg/kg body weight with daily increments till a 1 mg dose was reached. A total dose of 20 mg/kg was given initially and repeated if the parasites persisted. The investigations done before and after treatment were splenic or bone marrow aspiration, measurement of the spleen and liver size, body weight, total and differential white cell counts, haemoglobin level, total serum protein, blood urea, serum creatinine, serum potassium, blood sugar, serum alanine and aspartate transaminase, electrocardiography and a chest X-ray. The efficacy of treatment was assessed at the end of treatment and after 6 months of follow up. RESULTS: After treatment with amphotericin B, 298 (99%) of the patients had been cured of their disease as evidenced by the disappearance of fever, reduction of hepatosplenomegaly, clearance of the parasites from the spleen and bone marrow and an absence of relapse on 6 months of follow up. Two hundred and sixty-eight (89%) patients required 1 g of the drug, 24 (8%) required 1.5 g and 6 (2%) required 2 g. All patients had shivering and fever during the infusion. Two had a cardiac arrest from which they could not be revived. Other complications included anorexia, stomatitis, jaundice, hypokalaemia and a rise in blood urea. However, these were only mild and improved after treatment was stopped. CONCLUSION: Amphotericin B is an effective drug for patients with kala-azar unresponsive to treatment with sodium stibogluconate and pentamidine, but it should be administered under close medical supervision.

Efficacy of amphotericin B in multi-drug resistant kala-azar in children in first decade of life.

Fifty children in the first decade of life, and suffering from multiple drug resistant kala-azar, confirmed by demonstration of amastigotes in aspirates of bone marrow or spleen were treated with amphotericin B in gradually increasing dosage to a total dose of 20 mg/kg. All patients had classical features of severe kala-azar, and had taken more than one course of antimony and pentamidine, and three patients had taken one additional course of ketoconazole besides many courses of antimony and pentamidine. The clinical response started just after first infusion in 8 patients, and the patients became afebrile. By 5th infusion, all looked better and 18 patients became afebrile. By 15th infusion all patients were afebrile and cheerful. Their spleens became smaller and body weights and total white cell counts increased. Forty eight patients had parasitological cure at the end of treatment, and only 2 patients required an additional 5 infusions for parasitological cure. All patients were ultimately cured. No one relapsed within six months of follow up. All patients had shivering, rigor and rise of temperature on the day of infusion, which could be minimized with prior administration of low dose of hydrocortisone, but could not be eliminated. Eighteen patients had loose motions during treatment, while 14 patients had decrease in appetite which improved quickly when the treatment was over. Fourteen patients had transient rise of blood urea, in six patients serum creatinine also increased and 16 patients had a minor fall in serum potassium.(ABSTRACT TRUNCATED AT 250 WORDS)

Reactive arthritis complicating cryptosporidial infection.

Two cases of reactive arthritis in association with cryptosporidial enteritis in childhood are reported. Oocysts of cryptosporidium should be sought when arthritis complicates diarrhoeal illnesses.

Cryptosporidiosis in the West of Scotland.

During the two years 1986 and 1987 83 cases of cryptosporidiosis were identified by the finding of oocysts in the faecal samples submitted to a single microbiology laboratory. There were 58 children and 25 adults. Cryptosporidiosis was the commonest cause of gastrointestinal infection identified in children and the third commonest overall. Spring and autumn peaks were identified. The main symptoms were diarrhoea (median 10 days), vomiting (median seven days), abdominal pain (median seven days) and fever (median three days). A variety of other less common symptoms were noted including reactive arthritis. Three cases occurred during late pregnancy and the puerperium. Contact tracing supported both person-to-person transmission and an animal origin for cases within the group. Cryptosporidiosis is shown to be an important cause of traveller's diarrhoea. The incubation period was from two to 11 days.

Shedding of oocysts of Cryptosporidium in immunocompetent patients.

Forty nine patients (19 adults and 30 children) with oocysts of Cryptosporidium in their faeces had repeated stool specimens taken until oocysts could no longer be identified. They were found in the stools up to 35 days after the onset of symptoms in one patient, but most had stopped shedding them by 20 days. In 25 of the 49 patients in whom symptoms could be compared with the shedding of oocysts, 19 (76%) had symptoms corresponding to the shedding period while symptoms persisted in four (16%) after shedding had stopped.