Topical tofacitinib for atopic dermatitis: a phase IIa randomized trial.

BACKGROUND: Despite unmet need, 15 years have passed since a topical therapy with a new mechanism of action for atopic dermatitis (AD) has been approved. Janus kinase (JAK) inhibitor treatment effect via topical application in patients with AD is unknown. OBJECTIVES: Tofacitinib, a small-molecule JAK inhibitor, was investigated for the topical treatment of AD. METHODS: In this 4-week, phase IIa, randomized, double-blind, vehicle-controlled study (NCT02001181), 69 adults with mild-to-moderate AD were randomized 1:1 to 2% tofacitinib or vehicle ointment twice daily. Percentage change from baseline (CFB) in Eczema Area and Severity Index (EASI) score at week 4 was the primary end point. Secondary efficacy end points included percentage CFB in body surface area (BSA), CFB in EASI Clinical Signs Severity Sum Score, proportion of patients with Physician's Global Assessment (PGA) response and CFB in patient-reported pruritus. Safety, local tolerability and pharmacokinetics were monitored. RESULTS: The mean percentage CFB at week 4 in EASI score was significantly greater (P < 0·001) for tofacitinib (-81·7%) vs. vehicle (-29·9%). Patients treated with tofacitinib showed significant (P < 0·001) improvements vs. vehicle across all prespecified efficacy end points and for pruritus at week 4. Significant improvements in EASI, PGA and BSA were observed by week 1 and improvements in pruritus were observed by day 2. Safety/local tolerability were generally similar for both treatments, although more adverse events were observed for vehicle vs. tofacitinib. CONCLUSIONS: Tofacitinib ointment showed significantly greater efficacy vs. vehicle across end points, with early onset of effect and comparable safety/local tolerability to vehicle. JAK inhibition through topical delivery is potentially a promising therapeutic target for AD.

In vivo healing potential of Aegle marmelos in excision, incision, and dead space wound models.

The study incorporates the wound healing potential of Aegle marmelos fruit pulp extract (AME) on excision, incision, and dead space wound models in rats. AME (200 mg/kg) was administered orally once daily for variable days depending on the type of wound ulcer study. AME was studied for its wound breaking strength (incision wound), rate of contraction, period of epithelization and histology of skin (excision model), and granulation tissue free radicals, antioxidants, acute inflammatory marker, and connective tissue markers and deep connective tissue histology (dead space wound). Complete wound contraction and epithelization were observed at the 20th day after treatment with AME as compared to the 24th day in control rats. Mean epithelization period and scar area were decreased while wound breaking strength was increased with AME compared with control. Granulation tissue showed increased levels of collagen determinants (33.7 to 64.4%, P < 0.001) and antioxidants (13.0 to 38.8%, P < 0.05 to P < 0.001), whereas markers of oxidative stress (55.0 to 55.6%, P < 0.001) and myeloperoxidase (21.3%, P < 0.001) were decreased in AME treated group. A. marmelos seems to promote wound healing by enhancing connective tissue formation and antioxidants status with decrease in free radicals and myeloperoxidase having tissue damaging effects.

Healing effects of Aegle marmelos (L.) Correa fruit extract on experimental colitis.

Graded doses of 50% ethanolic extract of dried fruit pulp of Aegle marmelos (AME) (100, 200 and 400 mg/kg) daily for 14 days in acetic acid (AA)-induced colitis in rats showed 200 mg/kg of AME as an optimal effective dose against AA-induced colonic damage score and weight. This dose (200 mg/kg; po) was further studied in AA-induced colitis for its effects on various physical (mucous/blood in stool, food and water intake and body weight changes), histology, antibacterial activity and biochemical parameters like free radicals (nitric oxide and lipid peroxidation), antioxidants (superoxide dismutase, catalase and reduced glutathione) and myeloperoxidase (acute-inflammatory marker) activities in rat colonic tissue. AME decreased colonic mucosal damage and inflammation (macroscopic and microscopic), mucous/bloody diarrhea, fecal frequency and increased body weight affected in AA-induced colitis. AME showed significant antibacterial activity and enhanced the antioxidants but decreased free radicals and myeloperoxidase activities thereby decreasing tissue damage and inflammation and thus, affording ulcer healing. The above effects of A. marmelos authenticated its use in indigenous system of Medicine.

Emergencies in HIV--part 2.

In a short span of two and a half decades, HIV/AIDS has emerged as second largest killer disease that has affected mankind. The triple drug antiretroviral therapy (ART) has ensured a reasonably good quality of life to HIV infected individuals. Human immunodeficiency virus (HIV) infection is associated with several opportunistic infections/malignancies that may be life threatening and need quick intervention by health care workers. These emergencies could be related to opportunistic infections that are seen at presentation or that occur as the immune system gets weaker, or may bedue to HIV itself per se. The emergencies could also result from use of antiretroviral drugs like lactic acidosis, pancreatitis, bone marrow suppression and may include the immune reconstitution syndromes. The emergencies due to the opportunistic conditions and HIV per se had been dealt with in detail in the part 1, and this part describes various emergencies that could be encountered due to the administration of the anti retroviral treatment. Some patients may present due to emergencies as a result of co-administration of antiretroviral drugs with drugs used for treatment of some opportunistic infections like ATT etc.

The changing spectrum of severe falciparum malaria: a clinical study from Bikaner (northwest India).

BACKGROUND & OBJECTIVES: Recently there were reports from all over India about changing spectrum of clinical presentation of severe malaria. The present study was planned to study the same in the northwest India. METHODS: This prospective study was conducted on patients of severe malaria admitted in a classified malaria ward of a tertiary care hospital in Bikaner, Rajasthan (northwest India) during 1994 and 2001. It included adult patients of both sexes belonging to all age groups. The diagnosis of Plasmodium falciparum was confirmed by demonstrating asexual form of parasites in peripheral blood smear. All patients were treated with i.v./oral quinine. The specific complications were treated by standard WHO protocol. The data for individual complications for both the years were analysed by applying chi-square test. RESULTS: In a prospective study in 1994 the spectrum of complication was dominated by cerebral malaria (25.75%) followed by jaundice (11.47%), bleeding tendencies (9.59%), severe anaemia (5.83%), shock (5.26%), Acute respiratory distress syndrome-ARDS (3.01%), renal failure (2.07%) and hypoglycemia (2.07%) whereas in 2001 it was dominated by jaundice (58.85%) followed by severe anaemia (26.04%), bleeding tendencies (25.52%), shock (10.94%), cerebral malaria (10.94%), renal failure (6.25%), ARDS (2.08%) and hypoglycemia (1.56%). The sharp difference for presence of jaundice and severe anaemia in 2001 and cerebral malaria in 1994 was statistically significant. Similarly, the important cause of mortality in 2001 was multiple organ dysfunction syndrome (71.10%) with predominant presentation of jaundice and renal failure, whereas in 1994, it was cerebral malaria (77.96%). INTERPRETATION & CONCLUSION: The observation of changing spectrum of severe malaria in this study and a significant increase in presentation with jaundice as an important manifestation is highly essential for primary, secondary and tertiary level health care providers for proper diagnosis and management.

Signet ring cell carcinoma of ampulla of Vater in a young adult.

Signet ring cell carcinoma of the ampulla of Vater is extremely rare. The 7 cases reported earlier have been in older patients. We report a 32-year-old lady with this condition, who also had metastases in the bone marrow, vertebrae, lungs and liver.

Marihuana inhibits dihydrotestosterone binding to the androgen receptor.

Marihuana and its constitutents delta 9-tetrahydrocannabinol (delta 9-THC) and cannabinol (CBN) were tested for their ability to interact with the androgen receptor in rat prostate cytosol. Smoked marihuana condensate, delta 9-THC, and CBN inhibit specific binding of dihydrotestosterone (DHT) to the androgen receptor with a dissociatin constant of the inhibitors (Li) of 2.1-5.8 X 10(-7)M. in addition, other metabolites of delta 9-THC were also androgen antagonists. This data suggests that the anti-androgenic effects associated with marihuana use results, at least in part, from inhibition of androgen action at the receptor level.

The antiandrogenic effects of delta 1-testolactone (Teslac) in vivo in rats and in vitro in human cultured fibroblasts, rat mammary carcinoma cells, and rat prostate cytosol.

The antiandrogenic properties of delta 1-testolactone (17 alpha-oxa-D-homo-1,4-androstane-3,17-dione; Teslac) were investigated in vivo and in vitro. Teslac (75 mg/day for 7 days) inhibited the rise in ventral prostate weight induced by testosterone (T) (P less than 0.001), dihydrotestosterone (DHT) (P less than 0.05), and a combination of T plus 17 beta-estradiol (E2) (P less than 0.01) in immature castrate rats. Similar effects were seen on the seminal vesicles after T and T plus E2 (P less than 0.001). Teslac also decreased prostate and seminal vesicle weights in intact immature rats. The effects of Teslac were dose and time dependent. Teslac did not change the concentration of serum T or DHT. However, Teslac inhibited DHT binding to the androgen receptor (Ki = 2.5 +/- 0.8 X 10(-7) M) in cytosol of the rat prostate. Teslac also inhibited DHT binding to the androgen receptor in cultured human prepuce fibroblasts and cultured rat mammary tumor cells (Ki = 1.9 +/- 0.3 X 10(-5) M). The results indicate that Teslac, in addition to its antiaromatase activity, is an antiandrogen by virtue of its interaction with the androgen receptor.

Synthesis and characterization of oligodeoxynucleotides containing the major DNA adducts formed by 1,6- and 1,8-dinitropyrene.

[reaction: see text] An efficient method for the synthesis of oligonucleotides containing a site-specific DNA adduct formed by the carcinogens 1,6- and 1, 8-dinitropyrene has been developed. Palladium-catalyzed amination provided a straightforward route for the synthesis of aminonitropyrenes which, following separation, were reduced to the nitrosonitropyrenes. The N-hydroxyaminonitropyrene, generated in situ from each nitrosonitropyrene, was used successfully to introduce the dinitropyrene-derived DNA adduct at a defined site in an oligonucleotide.

Can alcohol promote aromatization of androgens to estrogens? A review.

Increased aromatization may be a mechanism for feminization of some male alcoholics, as well as for the reported increases in plasma estrogen levels in postmenopausal women subjected to moderate alcohol consumption. Alcohol consumption-related increases in estrogen levels may in turn be partially responsible for the associated decreased risk for coronary artery disease and osteoporosis, as well as for increased risk for breast cancer. The purpose of this review is to evaluate the literature to determine whether alcohol can promote aromatization of androgens to estrogens. In male rats, chronic heavy alcohol administration (36% of total calories=12-18 g/kg/day) led to increased aromatization of androgen in the liver, but the results were equivocal for the hypothalamus. In female rats, chronic heavy alcohol administration did not promote aromatization in the hypothalamus exposed to alcohol in utero. In human placental tissue, although ex vivo alcohol administration (less or more than 72 g/day) did not affect the rate of aromatization, in vitro incubation of choriocarcinoma cells with 5-50 mM of alcohol increased estradiol secretion, which could be due to increased aromatization. In in vitro human ovarian granulosa cell studies, alcohol increased, had no effect on, or decreased estradiol secretion, and in one study, 20 mM of alcohol significantly increased aromatization of androstenedione to estrogens. These results may not be fully relevant to normal human ovary because in both studies cells were heavily luteinized by gonadotropins. A study of ovariectomized rats shows that only heavy chronic alcohol intake (4.4 g/kg/day) for 10 weeks can increase plasma estradiol levels and uterine weight, which could be due to increased aromatization or delayed clearance of estradiol. In conclusion, chronic heavy alcohol administration can result in aromatization of androgens in male rat liver. It is not clear whether moderate alcohol intake can produce a similar effect in the liver nor whether alcohol can potentiate aromatization of androgens in other tissue or organs of male rats. In females, the available information is not adequate to evaluate the effect of alcohol on aromatization. Further studies are required in both genders to evaluate the ability of alcohol (moderate vs. heavy dose) to promote aromatization of androgens to estrogens.

Testicular response of non-breeding pheasants to human chorionic gonadotropin, chicken pituitary extract, and photoperiod.

This investigation was designed to compare the testicular response of non-breeding pheasants to human chorionic gonadotropin (HCG), chicken pituitary extract (CPE), and extended photoperiod exposure (20L:4D) by analyzing testicular weights, testicular histology, and plasma testosterone levels. Exposure to 20L:4D increased testicular weights and plasma testosterone levels significantly (P less than .01) and recovered spermatogenesis completely. Injections of CPE increased testicular weights (P less than .01) and recovered spermatogenesis partially, but had no significant effect on plasma testosterone levels. Effects of HCG were non-significant. It is suggested that either doses of HCG and CPE used in this study were not enough or non-breeding pheasants require pheasant gonadotropins for the complete recovery of testicular function.

Testosterone levels in the blood plasma of male chicken-pheasant hybrids.

Testosterone levels in the blood plasma of sterile male chicken-pheasant hybrids were compared with plasma testosterone levels of roosters and male pheasants, using radioimmunoassay. Mean values of testosterone in the roosters, male pheasants and chicken-pheasant hybrids during spring were 155.47 +/- 4.03, 24.29 +/- 1.55 and 0.68 +/- 0.05 ng./100 ml., respectively and the corresponding values for winter were 88.88 +/- 4.10, 0.61 +/- 0.04 and 0.76 +/- 0.07 ng./100 ml. The pheasant testes were inactive in winter but active in spring whereas the hybrid testes were inactive in winter and spring unlike those of roosters which were active during these seasons. The low levels of testosterone in hybrids during both seasons could be attributed to the impairment of steroid biosynthetic activity of the Leydig cells and may be causally related to the absence of secondary sexual characteristics and the interruption of spermatogenesis in chicken-pheasant hybrids.

Abortion in guinea pigs by Chlamydia psittaci isolates from natural sheep abortion.

Experimental model for chlamydial abortion was planned using pregnant guinea pigs to study whether the isolate of Chlamydia psittaci from natural cases of sheep abortion is able to cause experimental abortion in pregnant guinea pigs or not. Follow up and clinical observations like thermal reaction and haematological changes exhibited biphaic febrile response and marked leucopenia in both intraperitoneal group as well as intravaginal group. The laboratory examinations revealed presence of chlamydial intracytoplasmic inclusions in the impression smears of aborted foetal tissues. C. psittaci was reisolated successfully from all the aborted foetal tissues. It was observed that rate and severity of abortion were more in the intraperitoneal group as compared to intravaginal group. On correlating the results of clinical and laboratory examinations it was observed that guinea pig can be used as a suitable model for chlamydial abortion in future studies like cell mediate immune response and to see protective role of chlamydial vaccine, if any.

Evaluation of in vivo wound healing activity of Bacopa monniera on different wound model in rats.

Wound healing effects of 50% ethanol extract of dried whole plant of Bacopa monniera (BME) was studied on wound models in rats. BME (25 mg/kg) was administered orally, once daily for 10 days (incision and dead space wound models) or for 21 days or more (excision wound model) in rats. BME was studied for its in vitro antimicrobial and in vivo wound breaking strength, WBS (incision model), rate of contraction, period of epithelization, histology of skin (excision model), granulation tissue free radicals (nitric oxide and lipid peroxidation), antioxidants (catalase, superoxide dismutase, and reduced glutathione), acute inflammatory marker (myeloperoxidase), connective tissue markers (hydroxyproline, hexosamine, and hexuronic acid), and deep connective tissue histology (dead space wound). BME showed antimicrobial activity against skin pathogens, enhanced WBS, rate of contraction, skin collagen tissue formation, and early epithelization period with low scar area indicating enhanced healing. Healing effect was further substantiated by decreased free radicals and myeloperoxidase and enhanced antioxidants and connective tissue markers with histological evidence of more collagen formation in skin and deeper connective tissues. BME decreased myeloperoxidase and free radical generated tissue damage, promoting antioxidant status, faster collagen deposition, other connective tissue constituent formation, and antibacterial activity.

A case series of splenic infarction during acute malaria in northwest Rajasthan, India.

Malaria is a rare cause of splenic infarction. Only a few cases have been reported worldwide, mostly associated with Plasmodium falciparum infection. Here we report a series of four acute malaria patients with splenic infarction, two with P. vivax infection, one with P. falciparum and one with a mixed infection (P. vivax and P. falciparum). This small case series suggests that if a patient with malaria is complaining of left upper quadrant abdominal pain, pleuritic left lower chest pain and/or enlarging tender splenomegaly during treatment, splenic infarct should be suspected and managed accordingly to avoid further life-threatening complications.