Pharmacokinetics of rifabutin during atazanavir/ritonavir co-administration in HIV-infected TB patients.

BACKGROUND & OBJECTIVE: Rifabutin (RBT) is the rifamycin that is recommended to treat tuberculosis (TB) in HIV-infected individuals during combination antiretroviral therapy (ART) containing HIV protease inhibitors (PIs). We studied the pharmacokinetics of rifabutin at doses of 300 mg thrice weekly and 150 mg daily during concomitant atazanavir/ritonavir (ATZ/r) administration in adult HIV-infected TB patients treated in the Revised National TB Control Programme (RNTCP) in India. METHODS: This was a multi-centric study conducted in 45 adult HIV-infected TB patients, who were being treated for TB with a RBT-containing regimen and an antiretroviral treatment regimen with ATZ/r, at doses of 300 mg thrice-weekly (n = 36) or 150 mg daily (n = 9). Serial blood draws at pre-dosing and at 1, 2, 4, 6, 8, 12 and 24 hours after drug administration were done. Plasma RBT was estimated by high pressure liquid chromatography (HPLC). RESULTS: The peak concentration (Cmax) of both doses were within the therapeutic range (0.45-0.90 µg/ml) of RBT. Proportion of patients having Cmax above or below the therapeutic range and trough concentration (Cmin) below the minimum inhibitory concentration of RBT did not significantly differ between the two doses. TB treatment outcomes were also similar at both doses. CONCLUSIONS: This is the first and only study from India reporting on the pharmacokinetics of RBT at 300 mg thrice weekly and 150 mg daily doses. Both doses yielded similar plasma RBT concentrations, outcomes and were well tolerated. RBT can be administered at either doses during ATZ/r co-administration in HIV-infected patients with TB.

Castlemans disease in HIV infected patient from eastern India.

Castlemans disease is a rare lymphoproliferative disorder. We report a patient of Castlemans disease with advanced HIV infection who responded well to conventional HAART. This case is interesting because of the rarity of the disease in the eastern part of India and its good out come with antiretroviral therapy.

The synthesis and accumulation of polyamines in reproductive organs of the rat during pregnancy.

The pregnancy of the rat brings about profound changes of the accumulation, biosynthesis and biodegradtion of the polyamines putrescine, spermidine and spermine in the reproductive tissues. 1. In the ovary, the concentration of all polyamines increased markedly around the 12th day of pregnancy. In the uterus, only the concentration of spermine rose at that time. The concentration of purtrescine more than doubled in the fetal part of the placenta around the 15th day of pregnancy, while the low content of putrescine in the maternal placenta did not appreciably change during the progress of pregnancy. Both parts of rat placenta contained relatively high initial concentrations of spermine, which however, rapidly decreased until the term. 2. The activity of ornithine decarboxylase (EC 4.1.1.17) was remarkably high in the placental tissue. The fetal part of the placenta exhibited higher ornithine decarboxylase activity from the very beginning and the enzyme activity also remained at high levels throughout the pregnancy. The initially high orthine decarboxylase activity was very low in the uterus during the early days of pregnancy, however, rapidly increased a few days after the implantation. Uterine ornithine decarboxylase activity reached a maximum on day 12 to 14 of pregnancy and then swiftly decreased. 3. Both parts of the placenta contained high diamine oxidase (EC 1.4.3.6) activity, which, however, rapidly disappeared in the fetal part of the placenta. Although considerably decreasing, the activity of diamine oxidase still was remarkably high in the maternal placenta until the term. No diamine oxidase activity was found in the uterus of normally cycling rats. The enzyme activity was also undetectable in the uterus during the early pregnancy, but abruptly appeared on day 10 of pregnancy, reached a maximum around the 15th day of pregnancy, and therafter gradually decreased until the term. 4. The changes of activity of adenosylmethionine decarboxylase (EC 4.1.1.50) in the uterus and placental tissues resembled those changes found in ornithine decarboxylase activity. The activity of adenosylmethionine decarboxylase also rapidly decreased after day 12 of pregnancy. 5. Uterine diamine oxidase was partially purified (about 30-fold) and its substrate specificity was determined. Diamines putrescine, cadaverine and 1,3-diaminopropane served as most efficient substrates for the enzyme. Some evidence is presented as to indicate that also spermidine and spermine were oxidized by the enzyme, although at much slower rate than the diamines...

Type 1 and type 3 Gaucher disease in two siblings in a family: 2 unusual case reports.

Gaucher disease (GD) is an autosomal recessive disorder, characterized by lack of acid ß-glucosidase (glucocerebrosidase) enzyme resulting in accumulation of glucosylceramide in different organs. It is common in Ashkenazi Jews but rare in India. Around five hundred cases are identified and diagnosed in India. We are reporting two interesting cases of type 1 non-neuropathic and type 3 juvenile subacute neuropathic variant of adult Gaucher disease in two of three siblings in a family.

p-Amino salicylic acid - oxidized cellulose system: a model for long term drug delivery.

The mobilization of p-amino salicylic acid (PASA) on periodic oxidized cellulose (O.C) as a biocompatible carrier was investigated. The immobilization of the PASA is based on Schiff's base formation between the amino group of PASA and the aldehyde group of O.C. The in vivo and in vitro release of p-amino salicylic acid was studied. Such a system may be useful for the sustained delivery of the drugs in the body, since O.C. itself is a biosoluble carrier.

Histoplasmosis in eastern India: the tip of the iceberg?

Systemic histoplasmosis has various clinical presentations and is of especially concern in immunocompromised patients. A high index of suspicion is required for its diagnosis. A total of 38 cases had been reported from India up to 1996. The most frequent occurrence of cases was around Calcutta in eastern India where the previous case was detected 20 years earlier. However, we have diagnosed 5 cases in the past 2 years from eastern India which are reported here. These cases may indicate under-diagnosis and under-reporting of histoplasmosis in India. All 5 patients had disseminated disease with multisystem involvement including 2 with bilateral adrenal enlargement. Two were diabetic and only 1 patient was infected with HIV.

Reversibility with sodium bicarbonate of styrene maleic anhydride, an intravasal injectable contraceptive, in male rats.

A copolymer of styrene and maleic anhydride (SMA) was dissolved in dimethyl sulphoxide (DMSO) and injected into the lumen of the vas deferens of rats. The polymer was retained in the lumen for a period of more than 90 days. Sodium bicarbonate (10%), pH 8.9, was used to flush the polymeric material from the vas deferens lumen. The reversibility and patency of the vas deferens was thus obtained. Sodium bicarbonate proved to be an effective alternative to dimethyl sulphoxide for reversal.

Phase I clinical trial of an injectable contraceptive for the male.

Earlier studies on the rat and the monkey had demonstrated that an injection of styrene maleic anhydride (SMA) in a solvent vehicle of dimethyl sulphoxide (DMSO) into the lumen of the vas deferens is toxicologically safe and has contraceptive action. Phase I clinical trial was therefore undertaken on 38 male volunteers giving varying doses of SMA, ranging between 5 mg and 140 mg, into each vas deferens. A dose of 70 mg is the predicted therapeutic dose based on animal data. That the compound is within the vas deferens lumen during the period of the safety assessment is inferred from the effect on the spermatozoa count in ejaculates which reach azoospermic levels in the higher dose ranges. The treatment is well tolerated with only minimal side effects in a few cases and no long-term adverse effects.

PIP: 38 men living in Delhi, India, volunteered to participate in a Phase I Clinical Trial of an injectable contraceptive (styrene maleic anhydride [SMA] in a solvent vehicle of dimethyl sulphoxide [DMSO] aimed to assess the safety of DMSO-SMA in humans. Physicians injected the DMSO-SMA mixture into the lumen of each vas deferens. All their wives had already undergone tubal occlusion. Low doses (5-20 mg) of SMA did not reduce the sperm count. Sperm counts did not change until the dose reached 40 mg, suggesting that the polymer SMA stayed in the vas deferens. Azoospermia did not occur until the SMA dose reached 70 mg, the predicted therapeutic dose based on animal data. Azoospermia did not take place until 34-80 days postinjection in most men. All the men reported normal sexual activity 10 days after the injection. 1 man receiving 40 mg SMA experienced some pain in the scrotal region and moderate scrotal enlargement. Antiinflammatory drugs resolved the situation. Another man received 140 mg and his scrotum increased to twice its regular size. He also experienced bilateral tenderness of the spermatic cord and inguinal canal. Antibiotics and antiinflammatory drugs resolved the swelling. He may have experienced a hypersensitive reaction to SMA. At least 2 years after treatment, all but 1 subject were health and had no complaints. 1 subject had committed suicide for reasons other than the DMSO-SMA injection. No longterm adverse effects occurred, indicting that DMSO-SMA is safe.

Injectable non-occlusive chemical contraception in the male-I.

A new contraceptive technique has been proposed and tested. The method uses a novel polymer which when injected into the vas deferens, lowers the pH sufficiently kill the spermatozoa passing through. The polymer itself does not degrade in the process but can be flushed out to regain fertility. Experiments carried out on rats demonstrate the efficacy of the technique so as to have non-surgical, non-occlusive and reversible male contraception.

PIP: A radically new technique of male injectable nonocclusive chemical contraception is presented which is claimed to be reversible, not conducive to immunological reactions, nonsurgical, and nonocclusive. The method basically involves infusion of a chemical agent into the vas deferens, but its basic principle of operation differs significantly from standard chemical techniques. A novel polymer was fabricated which when injected into the vas deferens does not affect the lumen and lowers pH sufficiently to kill any spermatozoa passing through the vas. In addition, the polymer does not degrade in the process but can be removed by flushing to reverse the spermicidal effects of its insertion. In vitro studies showed the pH to be as low as 3.5. In addition, in vitro spermicidal action of the polymer was tested, and each time the polymerized sperm were unable to uptake dye, confirming their death. Fertility trials, utilizing albino rats, proved the efficacy of this polymer in vivo: rats were treated with either normal saline solvent only (dimethyl sulfoxide), or dissolved polymer for 180 days, and at the conclusion of the trial, the fertility of saline-treated rats had 0% fertility. This technique has the potential for easy reversibility while not affecting the patency of vas deferens.

Time-controlled injectable occlusion of the vas deferens.

An injectable method of obtaining vas deferens occlusion is presented. The agent used is styrene maleic anhydride (SMA) with dimethyl sulphoxide as the solvent. The special feature of the approach is that after a period of time, spermatozoa passage is spontaneously reestablished. By varying the dose of SMA administered, the interval between injection and restoration of spermatozoa flow can be regulated from as short a period as about 3 months to more than five years.

Contraception in male monkeys by intra-vas deferens injection of a pH lowering polymer.

A new male method of contraception by injecting a polymer, styrene-maleic anhydride (SMA), into the lumen of the vas deferens has been studied on rhesus monkeys. The polymer has the dual feature that it can occlude the vas deferens lumen and also it can inhibit the fertilising ability of spermatozoa by virtue of the pH lowering effect. Matings with females were carried out when the lumen was completely occluded giving azoospermia as well as with partial block and spermatozoa present in the semen. All matings were infertile. Data up to one year is presented. All indications are that the contraceptive effect will last for a considerably long period.

Phase II clinical trial of a vas deferens injectable contraceptive for the male.

Following up on an earlier clinical trial demonstrating the safety of an intra-vas deferens injection of a contraceptive drug named Risug, comprised of styrene maleic anhydride (SMA) in a solvent vehicle of dimethylsulphoxide (DMSO), a study to assess the contraceptive effectiveness of a specific dose (60 mg) of SMA bilaterally was planned and implemented. Male subjects and their wives with normal reproductive profiles were the volunteer subjects. The wives were not using any contraceptives. The results reconfirm the safety and show that for a period of at least 1 year, the treatment leads to azoospermia in the male and gives pregnancy protection.

PIP: A Phase I clinical trial documented the safety of an intra-vas deferens injection of a contraceptive agent (Risug) containing up to 140 mg of styrene maleic anhydride (SMA) in a solvent vehicle of dimethylsulfoxide. This Phase II study sought to determine whether a single injection of a fixed dose of SMA into the lumen of the vas deferens controls fertility for a period of at least 12 months. 12 male subjects whose wives were not using a contraceptive method were administered 60 mg of SMA bilaterally. This regimen produced sustained azoospermia in all 12 subjects, with no changes in other parameters over the course of the 12-month study period. Spermatozoa all along the length of the vas deferens appeared to be inactivated immediately following injection. No pregnancies were reported. The findings confirm the safety of this method and indicate that the treatment leads to azoospermia for at least 1 year.

Non-invasive reversal of intraluminal vas deferens polymer injection-induced azoospermia--technology.

AIM: The rationale and technique underlying a novel concept of non-invasive removal of an intravasal vas deferens polymeric contraceptive drug to reverse drug injection-induced azoospermia are explained. Thus the conventional methods of surgical exploration to remove vas deferens plugs and intravasal injection of solvents to flush out contraceptive drugs are to be replaced by steps which will be readily accepted by subjects. METHODS: The approach is based upon the non-invasive application of specific forces to various segments of the vas deferens so that non-sclerosing and non-tissue-adherent compounds, in particular styrene maleic anhydride (SMA) can be expelled. Forces are generated by palpation; percutaneous electrical stimulation; vibration application; and percussion. The forces help to propel the intravasal polymer towards the ejaculatory duct for expulsion during ejaculation. All aspects of the total technique are clinically acceptable, simple, atraumatic, unlikely to cause pain and discomfort even without tranquilizers, local or general anaesthetics. The procedure may be repeated several times in different sittings spaced apart by about one week to achieve adequate plug expulsion. RESULTS: Model experiments demonstrated the feasibility of the concept. The polymer was nonadherent and could be moved within the vas deferens by the application of specific forces. Sufficient removal was possible to enable spermatic fluid to be transported along a region previously occupied by the polymer. A corroborating subhuman primate study by an independent investigator has shown that the semen profile becomes normal following the reversal. CONCLUSION: Adoption of the new technique may provide a means of non surgical restoration of normal semen profile after a period of fertility control obtained by intravasal drug injection.

Effect of moderate & high loadings on the proteoglycans & water content of bovine knee joint articular cartilage.

Variations in proteoglycans and water content of the knee joint cartilage were found to occur when the joint was subjected to articulating motion under moderate and high loadings. It was found that at a moderate load of 150 kg there were an increase in the percentage of proteoglycans but the percentage decreased when the joint was articulated at a high loading of 300 kg. It has also been observed that the ratio of water content and the proteoglycans decreased at moderate load, whereas the ratio increased at high load. The observed changes in proteoglycans and water content in extracellular matrix with moderate and high loadings suggested that articular cartilage properties respond to mechanical stresses.

A simple and inexpensive clinical whole body counter.

The conventional radioisotope scanner has been used as a whole body counter. The background index of the system is 10.9 counts per minute per ml of sodium iodide crystal. The sensitivity and derived sensitivity parameters have been evaluated and found to be suitable for clinical studies. The optimum parameters for a single detector at two positions above the lying subject have been obtained. It has been found that for the case of 131I measurement it is possible to assay a source located at any point in the body with coefficient of variation less than 5%. To add to the versatility, a fixed geometry for in-vitro counting of large samples has been obtained. The retention values obtained by the whole body counter have been found to correlate with those obtained by in-vitro assay of urine and stool after intravenous administration of 51Cr-albumin.

Interplay of matrices in cartilage synovial fluid combine under moderate & high loadings.

Interplay of the constituents of the articular cartilage synovial fluid combine and its role was examined through the biochemical and rheological studies on bovine joints. The results showed an inverse relationship between the changes in the hyaluronic acid of synovial fluid and the proteoglycans content in articular cartilage together with alterations in the rheological properties of synovial fluid. The study indicated that the inter-movement of fluid solutes across the cartilage and synovial fluid may have an important role in the pathophysiology of osteoarthritis.

Multifactorial interactions in the aetiopathogenesis of EPH-Gestosis--a hypothesis.

The aetiopathogenesis of EPH-Gestosis or pre-eclampsia-eclampsia is still not clear. Although many hypotheses implicating environmental, nutritional, immunological, and genetic factors have been put forward, no hypothesis provides the scientific basis for the early spiral arterial degenerative changes, and incomplete physiological trophoblastic invasion of the spiral arteries, leading to a high utero-placental resistance with reduced blood flow remains unexplained. To get an insight into the basic pathogenesis of EPH-Gestosis, the following hypothesis has been proposed. The hypothesis considers an abnormal proliferation of the spiral vessels as the key factor in the pathogenesis of the high uteroplacental resistance and the endothelial dysfunctions in EPH-Gestosis. Further it is proposed that this proliferation is on account of the enhanced polymerization of the deficient DNA triggered by the high steroidal level and relatively low micronutrient level in EPH-Gestosis during the early formative stages of the placental circulation. Steroidal hormone helps in polymerization of the DNA, micronutrients exert a controlling influence through DNA synthesis on cell proliferation. A critical balance of hormone-micronutrients such as vitamin A, B12, folic acid, etc., therefore, seems necessary for normal cellular proliferation. It appears therefore that there probably exists an imbalance with a high estrogen and a relatively low micro-nutrient level in EPH-Gestosis, triggering off a process of abnormal spiral vessel proliferation. These abnormal vessels with a deranged endothelial function may prevent the second wave of normal trophoblastic invasion assumed to be important for the establishment of the low resistance uteroplacental circulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Understanding utero-placental blood flow in normal and hypertensive pregnancy through a mathematical model.

Normal development of utero-placental circulation is crucial not only for the survival and growth of the fetus in utero, but also for maternal well-being. Any disturbance or abnormality may reflect underlying pathology. Geometric conversion of a pre-pregnant spiral vessel into a divergent low-resistance vessel is believed to be responsible for the increased utero-placental blood flow in normal pregnancy. Known biomedical investigative techniques have failed to explain many such underlying haemodynamic changes taking place in the utero-placental system. Therefore, proper understanding of the system using a mathematical model has been found to be useful. The physiological fluid dynamic study is the first in this branch of physiology. Abnormal pressure gradient, axial velocity, volume flow and shear rate are obtained for various slowly changing geometries such as, tapering, divergence, local constrictions and sinusoidal tube for low Womersley parameters. The model can explain many enhanced patho-physiological changes, such as persistence or the appearance of local constriction in the utero-placental vessels. Such pathological changes are considered to be responsible for very high utero-placental resistance, leading to blood flow insufficiency in pre-eclampsia or intra-uterine growth retardations. It is believed that these changes may be caused by low shear rate on the pre-existing deranged or abnormal endothelium. Furthermore, this derangement is caused by an abnormal proliferation of either spiral vessels or the invading non-villous trophoblasts. Doppler flow study can explain and validate some of the theoretically derived flow velocity results. The study opens up a new area of research into utero-placental physiological fluid dynamics.

Computer as a group teaching aid for persons who are blind.

A concept has been formulated whereby a teacher in a classroom for students who are blind can communicate line diagrams and text directly to the students. This approach is based upon a single computer placed on the teacher's desk, with monitors on the students' desks. Access to the information displayed on the monitors is obtained by means of an optoelectronic sensor and vibrotactile output. Two versions of the sensor have been made--one for sensing line diagrams, and the other for Braille text. A simple, low-cost arrangement has also been designed by which students who are blind can prepare a hard copy of the diagrams from the monitor display. The special feature of the system is that it allows the teacher to convey information directly to the students, that is, diagrams and text that have been entered into the computer while the students are in the classroom. Information previously stored on floppy disks may also be communicated in this way. This methodology will overcome the current limitation where the teacher is able to hand out only embossed diagrams and text that have been previously prepared. Learning to use the new system can be accomplished in a short time, with the added advantage that the system is relatively inexpensive.

Set-covering diagnostic expert system for psychiatric disorders: the third world context.

This paper presents an implementation of the set-covering model for diagnosing psychiatric disorders. Such a model is useful as the basis for the inference mechanism of an expert system in that it provides a satisfactory solution to the difficult problem of multiple simultaneous disorders. The set covers have been formed through the 'diagonal search method' in which the combination of an element with the rest of the elements along the diagonals in the combination matrix was found to be adequate. 'Abductive logic' has been used to reach the possible final solution. Another feature of this expert system is its elicitation system. Provision has been made in the expert system for observations to be made and questions to be asked of the patient in difficult-to-elicit psychiatric signs. It makes this expert system usable by the non-expert clinicians. This has been specially designed in the context of third-world conditions. The system has been tested on cases given in the DSM-III case book with 100% success. However, the system's knowledge should be expanded and refined if it is to be used in psychiatric clinical practice.