In Vivo Therapeutic Efficacy of Chloroquine Alone or in Combination with Primaquine against Vivax Malaria in Kolkata,West Bengal,India, and Polymorphism in pvmdr1 and pvcrt-o Genes

Plasmodium vivax malaria, though benign, has now become a matter of concern due to recent reports of life-threatening severity and development of parasite resistance to different antimalarial drugs. The magnitude of the problem is still undetermined. The present study was undertaken to determine the in vivo efficacy of chloroquine (CQ) and chloroquine plus primaquine in P. vivax malaria in Kolkata and polymorphisms in the pvmdr1 and pvcrt-o genes. A total of 250 patients with P. vivax monoinfection were recruited and randomized into two groups, A and B; treated with chloroquine and chloroquine plus primaquine, respectively; and followed up for 42 days according to the WHO protocol of 2009. Data were analyzed using per-protocol analyses. We assessed polymorphisms of the pvmdr1 and pvcrt-o genes by a DNA-sequencing method. Out of the 250 patients recruited, 204 completed a 42-day follow-up period, 101 in group A and 103 in group B. In group A, the non-PCR-corrected efficacy of CQ was 99% (95% confidence interval [CI], 0.944 to 1.00), and in group B, all cases were classified as adequate clinical and parasitological response (ACPR). Day 3 positivity was observed in 11 (5.3%) cases. No specific mutation pattern was recorded in the pvcrt-o gene. Eight nonsynonymous mutations were found in the pvmdr1 gene, three of which were new. The Y976F mutation was not detected in any isolate. Chloroquine, either alone or in combination with primaquine, is still effective against P. vivax malaria in the study area. (The study protocol was registered in CTRI [Clinical Trial Registry-India] of the Indian council of Medical Research under registration no. CTRI/2011/09/002031.)     

In Vitro and In Vivo Efficacy of β-Lactams against Replicating and Slowly Growing/Nonreplicating Mycobacterium tuberculosis

Beta-lactams, in combination with beta-lactamase inhibitors, are reported to have activity against Mycobacterium tuberculosis bacteria growing in broth, as well as inside the human macrophage. We tested representative beta-lactams belonging to 3 different classes for activity against replicating M. tuberculosis in broth and nonreplicating M. tuberculosis under hypoxia, as well as against streptomycin-starved M. tuberculosis strain 18b (ss18b) in the presence or absence of clavulanate. Most of the combinations showed bactericidal activity against replicating M. tuberculosis, with up to 200-fold improvement in potency in the presence of clavulanate. None of the combinations, including those containing meropenem, imipenem, and faropenem, killed M. tuberculosis under hypoxia. However, faropenem- and meropenem-containing combinations killed strain ss18b moderately. We tested the bactericidal activities of meropenem-clavulanate and amoxicillin-clavulanate combinations in the acute and chronic aerosol infection models of tuberculosis in BALB/c mice. Based on pharmacokinetic/pharmacodynamic indexes reported for beta-lactams against other bacterial pathogens, a cumulative percentage of a 24-h period that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (%T_MIC) of 20 to 40% was achieved in mice using a suitable dosing regimen. Both combinations showed marginal reduction in lung CFU compared to the late controls in the acute model, whereas both were inactive in the chronic model.     

Diazepam: effect on multiple electroacupuncture-induced changes in regional GABA of mammalian central nervous system

Single-dose diazepam (5 mg/kg i.p.) which increases central GABAergic activity alone normalizes the 6 multiple electroacupuncture (EA) (10 Hz, 1 volt, 10 min/day)-induced inhibition of GABAergic activity in Th and PM and thus reduces the EAA of adult male albino rats (120 +/- 10 g). On the contrary, single diazepam (5 mg/kg, i.p.) treatment to 15 multiple EA-(10 Hz, 1 volt, 10 min/day) exposed rats normalizes the 15 multiple EA-induced increase in thalamic GABAergic activity and fails to alter inhibition of GABAergic activity in CC and SC of 15 multiple EA-exposed rats. These results, thus, may be well correlated with the disinhibition of the 15 multiple EA-induced inhibition of analgesic response (assessed in terms of tail flick latency) with single diazepam treatment.     

Reactive oxygen intermediates and reactive nitrogen intermediates in copper intrauterine device users.

The mechanism of action of copper in copper intrauterine devices (Cu IUD) as an antimicrobial agent is not well understood. Copper and iron are supposed to be responsible for release of reactive oxygen intermediates (ROI) and reactive nitrogen intermediates (RNI), which are very active in the presence of infection. The copper in a copper IUD could be responsible for limiting pelvic inflammatory disease. The present study was composed of 20 IUD seekers in whom ROI and RNI were studied before insertion of Cu IUD and then at 1, 4, and 12 weeks afterward. ROI showed a rise after insertion, whereas RNI showed a steady decline. Hence, it is presumed that the rise in ROI could be responsible for both the bactericidal effect of Cu IUD and also for the fall in RNI.     

Effect of oxotremorine on the response of antidromically activated Renshaw cells in decerebrate cats

Summary In intercollicular decerebrate cats, some of which were made spinal in addition, the effect of oxotremorine (intravenous injection, 10–30 g/kg) was tested on antidromically activated Renshaw cells. Methylatropine premedication prevented the otherwise often fatal drop in blood pressure; ipsilateral dorsal roots L6-S1 and contralateral hindlimb nerves were cut to exclude segmental receptor interference. During supramaximal stimulation of ventral root L7 or the gastrocnemius nerves, an increase of activity ranging from 10–110% was observed. The drug occasionally evoked spontaneous discharges in Renshaw cells, or enhanced activity already present. Alpha motoneuron activity decreased in most cases. The interaction of oxotremorine with atropine and eserine was also investigated on Renshaw cells. Our results suggest that one of the effects of oxotremorine may be a disbalance between motor output and recurrent inhibition.Dr. Ganguly received support from the CSIR-DAAD Exchange of Scientists Programme.     

Electroacupuncture and its effect on rat hepatic functions

The effect of single, acute (7 pulses/sec., 0.75 volt) and chronic (4 pulses/sec., 0.75 volt) electroacupuncture (EA) treatment on alternate days for a period of 21 days on hepatic functions of rats were studied at cellular and subcellular levels. The points used for EA were Shenshu, Dachangshu and Zusanli. After chronic treatment, (a) protein, RNA, phospholipid, and cholesterol contents of whole liver and liver microsomal fraction increased significantly, (b) liver microsomal G-6-Pase activity increased significantly, (c) microsomal lipid peroxidation value decreased, (d) lipase activity increased. After acute treatment, (e) phospholipid, and cholesterol contents of the whole liver and liver microsomal fraction increased significantly, (f) liver microsomal G-6-Pase activity increased significantly, (g) liver microsomal lipid peroxidation value decreased, (h) GPT and lipase activity of liver increased. The parameters unchanged in acute treatment were as follows: (i) protein, RNA content, (j) GOT activity of the liver, (k) SGOT and SGPT activity, (1) hepatic triglyceride. The parameters unchanged in chronic treatment were as follows: (m) GOT and GPT activity of the liver, (n) SGOT and SGPT activity, (o) hepatic triglyceride. No apparent harmful effect of EA on rat hepatic functions is obvious from present study.     

Juxtaglomerular cells in renal angiomyolipoma. Ultrastructural observation

We have studied a case of renal angiomyolipoma by electron microscopy and found juxtaglomerular cells with typical rhomboid and spherical granules, in addition to smooth muscle cells, fat cells, and abnormal blood vessels. To our knowledge, this is the first ultrastructural demonstration of juxtaglomerular cells in renal angiomyolipoma.     

Effect of CP-20,961, an interferon inducer, on upper respiratory tract infections due to rhinovirus type 21 in volunteers.

Topically administered CP-20,961 is known to stimulate nasal interferon. Studies in volunteers given the drug prior to challenge with rhinovirus have yielded both fairly good results and only fair or poor results. This study was undertaken in an attempt to settle the differences between the results of these trials and to evaluate the possible effectiveness of CP-20, 961 when given after virus challenge. Sixty volunteers were randomly divided into four groups. One group received placebo, the second received the drug on the day before and the day of challenge, the third was given the drug for two days beginning 24 hr after challenge, and the fourth received the drug for two days beginning 48 hr after challenge. The average number and severity of symptoms in the group that received CP-20,961 prior to challenge were about half of those in the control group. There was no decrease, however, in the number and severity of symptoms in the groups that received the drug after challenge.     

Possible involvement of the GABAergic system in dopaminergic-cholinergic interactions in electroacupuncture-induced analgesia

The involvement of the GABA system in dopamine-acetylcholine interactions in electroacupuncture induced analgesia (EAA), measured in terms of tail flick latency (TFL) test, was studied with administration of the GABA receptor agonist, muscimol (1 mg/kg, i.p.); antagonist, bicuculline (2 mg/kg, i.p.); GABAmimetic drug, ethanolamine-O-sulfate (EOS) (2 mg/kg, s.c.) or the drugs stimulating or inhibiting acetylcholine and dopamine receptors activity to rats exposed to electroacupunture (EA). All the drugs were administered prior to EA (10 Hz, 1 volt) exposure (2-15 min). Results observed under the above conditions suggest that the cholinergic system has a direct inhibitory role on EAA and the dopaminergic system mediates its action via the cholinergic system. A decrease in EAA with both the GABA receptor agonist and antagonist and tremendous increase of EAA with the gabamimetic drug, EOS, showed that GABA receptors may not be directly involved in EAA. Further (a) gradual withdrawal of muscimol, bicuculline or physostigmine induced decrease in EAA with the increase in duration of EA exposure; (b) the characteristic changes in EAA observed with the coadministration of (i) L-DOPA + carbidopa + muscimol (ii) atropine + muscimol; and (c) no significant change in bicuculline + physostigmine induced inhibition of EAA with the increase in duration of EA exposure suggest that some inhibitory substance(s) may be released during EA which may inhibit the GABA system and finally cholinergic activity through the activation of dopaminergic neurone.