Acute Kidney Injury in Cirrhosis: Baseline Serum Creatinine Predicts Patient Outcomes.

OBJECTIVES: The International Ascites Club (IAC) recently defined Stage 1 acute kidney injury (AKI) for cirrhosis as an acute increase in serum creatinine (SCr) by ≥0.3 mg/dl or by ≥50% in <48 h from a stable value within 3 months. The baseline SCr may influence AKI risk and patient outcomes. The objective of this study is to determine in cirrhosis whether the baseline SCr has any effect on the in-hospital AKI course and patient survival. METHODS: North American Consortium for the Study of End-Stage Liver Disease is a consortium of tertiary-care hepatology centers prospectively enroling non-elective cirrhotic inpatients. Patients with different baseline SCr levels (≤0.5, 0.51-1.0, 1.01-1.5, >1.5 mg/dl) were evaluated for the development of AKI, and compared for AKI outcomes and 30-day survival. RESULTS: 653 hospitalized cirrhotics (56.7±10years, 64% men, 30% with infection) were included. The incidence of AKI was 47% of enrolled patients. Patients with higher baseline SCr were more likely to develop AKI, with significantly higher delta and peak SCr (P<0.001) than the other groups, more likely to have a progressive AKI course (P<0.0001), associated with a significantly reduced 30-day survival (P<0.0001). Multivariate logistic regression showed that the delta SCr during an AKI episode to be the strongest factor impacting AKI outcomes and survival (P<0.001), with a delta SCr of 0.70 mg/dl having a 68% sensitivity and 80% specificity for predicting 30-day mortality. CONCLUSIONS: Admitted cirrhotic patients with higher baseline SCr are at higher risk for in-hospital development of AKI, and more likely to have AKI progression with reduced survival. Therefore, such patients should be closely monitored and treated promptly for their AKI.

Overt hepatic encephalopathy: development of a novel clinician reported outcome tool and electronic caregiver diary.

Clinical management and clinical trials of patients with overt hepatic encephalopathy (OHE) are compromised by lack of standardized and reproducible tools for its clinical diagnosis or for caregiver (CG) identification of OHE manifestations which merit medical evaluation. Using an iterative Delphi method, Steering Committee and international hepatologist panel, the West Haven (WH) scale was modified to develop and operationalize a clinician tool for OHE identification and grading (HE Grading Instrument, HEGI™). Major diagnostic criteria included disorientation to time, place, and person, asterixis, lethargy, and coma. Minimum HEGI requirements for OHE diagnosis included: (1) disorientation, or (2) presence of both lethargy and asterixis, or (3) coma. Inter- and intra-rater HEGI reproducibility were 97 % and 98 %, respectively. When applied to a phase II clinical trial population of 178 patients with 388 OHE episodes, HEGI demonstrated excellent concordance with investigator judgement. Additionally, a multi-stage study was conducted to develop a daily CG e-diary, based on OHE manifestations recognizable by CG including speech difficulties, unusual behavior, forgetfulness, confusion, disorientation and level of consciousness. The e-diary was designed for use on smart phone, laptop or desktop, utilized branching logic and skip patterns, incorporated automatic daily completion reminders and real time alerts to clinical sites to facilitate daily standardized CG input and was found to be user friendly and understandable. The HEGI and e-diary, which were developed using methodology accepted by regulatory authorities, are designed to facilitate the design and interpretation of clinical trials for OHE and improve outcomes for OHE patients in clinical practice.

Expert consensus on the diagnosis and treatment of end-stage liver disease complicated by infections.

End-stage liver disease (ESLD) is a life-threatening clinical syndrome and when complicated with infection the mortality is markedly increased. In patients with ESLD, bacterial or fungal infection can induce or aggravate the occurrence or progression of liver decompensation. Consequently, infections are among the most common complications of disease deterioration. There is an overwhelming need for standardized protocols for early diagnosis and appropriate management for patients with ESLD complicated by infections. Asia Pacific region has the largest number of ESLD patients, due to hepatitis B and the growing population of alcohol and NAFLD. Concomitant infections not only add to organ failure and high mortality but also to financial and healthcare burdens. This consensus document assembled up-to-date knowledge and experience from colleagues across the Asia-Pacific region, providing data on the principles as well as evidence-based current working protocols and practices for the diagnosis and treatment of patients with ESLD complicated by infections.

Beta-blockers in hospitalised patients with cirrhosis and ascites: mortality and factors determining discontinuation and reinitiation.

BACKGROUND: It has been suggested that beta-blockers may increase mortality in patients with cirrhosis and refractory ascites but the effect of beta-blockers discontinuation or reinitiation has not been examined. AIMS: To compare, in hospitalised patients with cirrhosis and ascites, the effect of BB on survival and to examine the effect/predictors of beta-blockers discontinuation and reinitiation. METHODS: Sub-analysis of NACSELD (North American consortium for the study of end-stage liver disease, database containing prospective data on hospitalised patients with cirrhosis) data from 7 centres enrolling >100 patients with ascites. Data on BB discontinuation and reinitiation were collected by chart review. RESULTS: Seven hundred and sixteen patients, 307 (43%) on beta-blockers at admission and 366 (51%) with refractory ascites, were followed to death or hospital discharge. Beta-blocker use was associated with a lower white blood cell count at admission. Beta-blocker use in hospitalised patients with ascites was not associated with a higher mortality, even in those with refractory ascites. No significant changes in mean arterial pressure (MAP) were observed between groups. Discontinuation of beta-blockers (49%) was driven by low MAP, infection and acute kidney injury at time of discontinuation but was not associated with a higher mortality. Beta-blocker reinitiation occurred in 40% prior to discharge and was mainly driven by an increase in MAP. CONCLUSIONS: Beta-blocker use is safe in patients with cirrhosis and ascites (including those with refractory ascites) provided beta-blockers are discontinued in the presence of a low MAP and reinitiated once MAP reincreases. A potentially beneficial anti-inflammatory effect of beta-blockers is suggested.

Chronic opioid use is associated with altered gut microbiota and predicts readmissions in patients with cirrhosis.

BACKGROUND: Opioid use is epidemic in cirrhosis, which could precipitate hepatic encephalopathy (HE) potentially through gut dysbiosis and inflammation. AIM: To define the effect of opioids on readmissions and on gut microbiota composition and functionality. METHODS: Cohort 1 had 200 cirrhotic in-patients (with/without opioid use) followed prospectively through the index hospitalisation and 6 months post discharge. Readmissions (HE-related/unrelated) were compared between patients discharged on opioids compared to the rest, including using a multi-variable analysis. Cohort 2 consisted of 72 cirrhotics on chronic opioids who were age/model for end-stage liver disease (MELD) and prior HE-balanced with 72 cirrhotics not on opioids. Stool microbiota composition (multi-tagged sequencing), predicted functionality (PiCRUST), endotoxemia and systemic inflammation (IL-6, IL-17) were compared. RESULTS: Cohort 1: Chronic opioid use was statistically similar between those admitted with/without HE, and was judged to be an HE precipitant in <5% of cases during the index hospitalisation. Of the 144 patients alive at 6 months, 82 were readmitted. The opioid users had a significantly higher all cause (69% vs. 48%, P = 0.008), but not HE-related readmissions (30% vs. 41%, P = 0.30). On regression, opioid therapy and female gender were predictive of readmission independent of MELD score and previous HE. Cohort 2: Significant dysbiosis was noted in the opioid cohort, especially in HE+opioid patients with lower autochthonous taxa and Bacteroidaceae relative abundance. PiCRUST showed highest aromatic amino acid and endotoxin production in opioid users. Opioid users also had higher endotoxemia and IL-6 but not IL-17. CONCLUSION: Chronic opioid use in cirrhosis is associated with increased endotoxemia, dysbiosis and all-cause readmissions.

In silico structure-based design of a potent and selective small peptide inhibitor of protein tyrosine phosphatase 1B, a novel therapeutic target for obesity and type 2 diabetes mellitus: a computer modeling approach.

Protein Tyrosine Phosphatase 1B (PTP1B) has been shown to be a negative regulator of insulin signaling by dephosphorylating key tyrosine residues within the regulatory domain of the beta-subunit of the insulin receptor. Recent gene knockout studies in mice have shown the mice to have increased insulin sensitivity and improved glucose tolerance. Furthermore, these mice also exhibited a resistance to diet induced obesity. Inhibitors of PTP1B would have the potential of enhancing insulin action by prolonging the phosphorylated state of the insulin receptor. In addition, recent clinical studies have shown that the haplotype ACTTCAG0 of the PTPN1 gene, which encodes PTP1B, is a major risk contributor to type 2 diabetes mellitus (T2DM). Thus, there is compelling evidence that small molecule inhibitors of PTP1B may be effective in treating insulin resistance at an early stage, thereby leading to a prevention strategy for T2DM and obesity. Based on the crystal structure of the complex of PTP1B with a known inhibitor, we have identified a tetrapeptide inhibitor with the sequence WKPD. Docking calculations indicate that this peptide is as potent as the existing inhibitors. Moreover, the peptide is also found to be selective for PTP1B with a greatly reduced potency against other biologically important protein tyrosine phosphatases such as PTP-LAR, Calcineurin, and the highly homologous T-Cell Protein Tyrosine Phosphatase (TCPTP). Thus the designed tetrapeptide is a suitable lead compound for the development of new drugs against type 2 diabetes and obesity.

Postoperative management of noniatrogenic traumatic bile duct injuries: role of endoscopic retrograde cholangiopancreaticography.

BACKGROUND: Endoscopic therapy for iatrogenic bile duct injuries is well established. Abdominal trauma-related biliary injuries, however, are complex in nature. The role of endoscopic therapy for these patients needs further evaluation. METHODS: A retrospective study investigated nine patients who had surgery for abdominal trauma (4 gunshot, 4 crush, and 1 stab injury), presented postoperatively with noniatrogenic biliary injuries, and underwent endoscopic retrograde cholangiopancreaticography (ERCP). RESULTS: The ERCP was successful for all the patients. Eight patients had significant bile leak at intra- or extra-hepatic sites, and one patient was discovered to have complete cutoff of the common hepatic duct. All bile leaks were treated successfully using biliary sphincterotomy with or without transpapillary stenting. No complications of ERCP were observed. CONCLUSIONS: In this case series, ERCP was found to be useful as a diagnostic and therapeutic method for managing noniatrogenic traumatic biliary injuries in patients who had undergone previous surgery for abdominal trauma. The ERCP results were similar to those for iatrogenic bile duct injuries.

Review article: potential mechanisms of action of rifaximin in the management of hepatic encephalopathy and other complications of cirrhosis.

BACKGROUND: Progressive gut milieu (microbiota) changes occur in patients with cirrhosis and are associated with complications [e.g. hepatic encephalopathy (HE)]. AIM: To examine the role of rifaximin in the management of HE and other complications of cirrhosis, including potential mechanisms of action and the need for future studies. METHODS: A literature search was conducted using the keywords 'rifaximin', 'hepatic encephalopathy', 'ascites', 'variceal bleeding', 'peritonitis', 'portal hypertension', 'portopulmonary hypertension' and 'hepatorenal syndrome'. RESULTS: The nonsystemic agent rifaximin reduces the risk of HE recurrence and HE-related hospitalisations in cirrhosis. In patients with cirrhosis, rifaximin modulates the bacterial composition of the gut microbiota without a consistent effect on overall faecal microbiota composition. However, rifaximin can impact the function or activities of the gut microbiota. For example, rifaximin significantly increased serum levels of long-chain fatty acids and carbohydrate metabolism intermediates in patients with minimal HE. Rifaximin also favourably affects serum proinflammatory cytokine and faecal secondary bile acid levels. CONCLUSIONS: The gut microenvironment and associated microbiota play an important role in the pathogenesis of HE and other cirrhosis-related complications. Rifaximin's clinical activity may be attributed to effects on metabolic function of the gut microbiota, rather than a change in the relative bacterial abundance.

HCV eradication does not impact gut dysbiosis or systemic inflammation in cirrhotic patients.

BACKGROUND: Eradication of hepatitis C virus (HCV) is increasing but its residual impact on the pro-inflammatory milieu in cirrhosis, which is associated with gut dysbiosis, is unclear. AIM: To define the impact of sustained virological response (SVR) on gut dysbiosis and systemic inflammation in HCV cirrhosis patients. METHODS: Cirrhotic out-patients with HCV with/without SVR (achieved >1 year prior) and age-matched healthy controls underwent serum and stool collection. Serum was analysed for IL-6, TNF-α and endotoxin while stool microbiota analysis was performed using multitagged pyrosequencing. Microbial comparisons were made using UNIFRAC and cirrhosis dysbiosis ratio (lower score indicates dysbiosis). Comparisons were performed between cirrhotics with/without SVR and controls vs. cirrhotic patients. RESULTS: A total of 105 HCV cirrhotics and 45 age-matched healthy controls were enrolled. Twenty-one patients had achieved SVR using pegylated interferon + ribavrin a median of 15 months prior. No significant differences on demographics, cirrhosis severity, concomitant medications or diabetes were seen between cirrhotics with/without SVR. There was no significant difference in overall microbiota composition (UNIFRAC P = 0.3) overall or within specific microbial families (cirrhosis dysbiosis ratio median 1.3 vs. 1.0, P = 0.45) between groups with/without SVR. This also extended towards IL-6, TNF-α and endotoxin levels. Both cirrhosis groups, however, had significant dysbiosis compared to healthy controls [UNIFRAC P = 0.01, cirrhosis dysbiosis ratio (1.1 vs. 2.9, P < 0.001)] along with higher levels of endotoxin, IL-6 and TNF-α. CONCLUSIONS: Gut dysbiosis and a pro-inflammatory systemic milieu, are found in HCV cirrhosis regardless of SVR. This persistent dysbiosis could contribute towards varying rates of improvement after HCV eradication in cirrhosis.

Prolonged remission from hepatic encephalopathy with rifaximin: results of a placebo crossover analysis.

BACKGROUND: Rifaximin therapy reduced risk of hepatic encephalopathy (HE) recurrence and HE-related hospitalisations during a 6-month, randomised, placebo-controlled trial (RCT) and a 24-month open-label maintenance (OLM) study. However, the impact of crossover from placebo to rifaximin therapy is unclear. AIM: To study the impact of crossing over from placebo to rifaximin treatment on breakthrough HE and hospitalisation rates using a within-subjects design. METHODS: Adults with cirrhosis and history of overt HE episodes, currently in HE remission, received placebo during the RCT and crossed over to rifaximin 550 mg twice daily during the OLM study. Rate of breakthrough overt HE episodes, hospitalisations and incidence and rate of adverse events (AEs) were analysed during RCT and first 6 months of OLM. RESULTS: Of 82 patients randomised to placebo in the RCT who crossed over to the OLM study, 39 experienced an HE episode during the RCT compared with 14 during the OLM study (P < 0.0001). Significantly lower rates of HE events were observed with rifaximin treatment compared with placebo treatment (P < 0.0001). Rates of HE-related hospitalisation were numerically lower during rifaximin treatment compared with placebo treatment, although not significant. Rates of most common AEs, serious AEs and infection-related AEs were similar between the two treatments. CONCLUSIONS: This analysis confirms the repeatability of results from the RCT on safety and efficacy of rifaximin 550 mg twice daily in reducing the risk of hepatic encephalopathy recurrence, and suggests these findings are translatable outside of a rigorous, controlled trial setting.

Apolipoprotein A-I, A-II, B, C-II, and C-III in children with insulin-dependent diabetes mellitus.

This study was conducted to determine whether changes in the levels of plasma apolipoproteins (apo) A-I, A-II, B, C-II, and C-III, along with cholesterol and triglycerides, could provide additional information on these parameters in relation to the control of glycemia. Plasma and lipoprotein lipids and apolipoprotein levels were measured in 123 insulin-dependent diabetic children (4- to 12-years-old), classified into good, fair, and poor diabetic control based on HbA1c and fructosamine levels, and in 62 comparable healthy controls. Total cholesterol, very low density lipoprotein cholesterol, and low density lipoprotein cholesterol, as well as total triglycerides, very low density lipoprotein, low density lipoprotein, and high density lipoprotein (HDL) triglycerides, and apo B and apo C-III were increased significantly in children with fair and poor diabetic control. While in diabetic children with good control, only very low density lipoprotein cholesterol was elevated significantly compared with healthy control subjects. Conversely, the levels of cholesterol in HDL, HDL2, HDL3, and apo A-I were decreased significantly in the three diabetic groups, but apo A-II and apo C-II did not change. We conclude that in children with insulin-dependent diabetes mellitus, abnormalities in plasma lipid, lipoprotein, and apolipoprotein levels occur, the extent of which depends on the degree (extent) of glycemic control (the poorer the control the more substantial the abnormality). We suggest that measurement of apo C-III level along with apo B and apo A-I in these patients may be a sensitive indicator to alterations in glycemic control.

Environmental release of chemicals and reproductive ecology.

Reproductive ecology is defined as "the study of causes and mechanisms of the effects of environmental risk factors on reproductive health and the methods of their prevention and management." Major areas of concern, within the purview of this paper, relate to adverse pregnancy outcomes, effects on target tissues in the male and the female, and alterations in the control and regulatory mechanisms of reproductive processes. Teratogenic potential of chemicals, released as a result of accidents and catastrophes, is of critical significance. Congenital Minamata disease is due to transplacental fetal toxicity caused by accidental ingestion of methyl mercury. Generalized disorders of ectodermal tissue following prenatal exposure to polychlorinated biphenyls have been reported in Taiwan and Japan. The Bhopal gas disaster, a catastrophic industrial accident, was due to a leak of toxic gas, methyl isocyanate (MIC), in the pesticide manufacturing process. The outcome of pregnancy was studied in female survivors of MIC exposure. The spontaneous abortion rate was nearly four times more common in the affected areas as compared to the control area (24.2% versus 5.6%; p < 0.0001). Furthermore, while stillbirth rate was found to be similar in the affected and control areas, the perinatal and neonatal mortality rates were observed to be higher in the affected area. The rate of congenital malformations in the affected and control areas did not show any significant difference. Chromosomal aberrations and sister chromatid exchange (SCE) frequencies were investigated in human survivors of exposure. The observed SCE frequencies in control and exposed groups indicated that mutagenesis has been induced. Strategies for the management, prediction, and preventability of such disasters are outlined.

High-dose vitamin E supplementation does not diminish ribavirin-associated haemolysis in hepatitis C treatment with combination standard alpha-interferon and ribavirin.

BACKGROUND: Ribavirin is associated with haemolytic anaemia. Antioxidants have been reported to decrease severity of this anaemia. AIM: To determine effect of vitamin E supplementation on ribavirin-associated haemolysis in chronic hepatitis C treated with standard alpha-interferon and ribavirin. METHODS: Fifty-one naive chronic hepatitis C patients were randomized to receive either alpha-interferon/ribavirin therapy (control) or therapy plus vitamin E 800 IU b.d. with 24-week follow-up. Alanine aminotransferase ALT, haemoglobin and reticulocyte percentage were monitored. Symptoms and health-related quality of life were also monitored at each visit. RESULTS: Forty-seven subjects were treated (27 vitamin E /20 controls). Thirteen withdrew because of adverse effects or non-compliance. Groups were similar in demographics, genotype and baseline lab indices. Comparison with baseline, treatment and follow-up values showed a significant haemoglobin and ALT reduction in both groups. There was no significant difference in haemoglobin and reticulocyte percentage between groups. Sustained viral response was not significantly different between vitamin E (11/18) and control (6/16) groups. Three patients required ribavirin dose-reduction in the vitamin E group compared with two controls. Health-related quality of life during and end-of-treatment was not different between groups. CONCLUSIONS: Vitamin E supplementation alone during standard alpha-interferon and ribavirin therapy does not appear to diminish ribavirin-associated haemolysis.

Adrenocortical function in experimental protein malnutrition.

Adrenocorticoid activity was investigated in experimentally induced protein malnutrition in Rhesus monkeys. Control studies were carried out in the same animals before inducing protein malnutrition. Plasma cortisol levels were elevated in the protein malnourished state. There was a total abolition of the diurnal rhythm of cortisol secretion. Fasting hypoglycemia was also observed in the protein malnourished state. It is concluded that increased adrenocorticoid activity and sustained steroidogenesis result from protein deficiency. Hypoglycemia may be an important stimulus, in addition to the metabolic stress imposed by the protein deprivation. The recognition of increased adrenocorticoid activity is important in a protein-deficient host, since the defense against infections might be impaired in such a situation.

Alcohol abuse in a rural community in India. Part I: Epidemiological study.

By systematic sampling of households after two stage proportionate random sampling of villages, a total of 4670 persons above 15 years of age were selected from the rural areas of Ajmer district in Rajasthan, India, to estimate the prevalence rate of alcohol abuse and to study its socio-demographic correlates (Part I) and the pattern and characteristics of use (Part II, submitted). The data on these aspects were collected through pre-tested questionnaires. The results showed that prevalence of alcohol abuse in the sample was 24.7% (36.1% for males and 13.4% for females) and the percentage of dependents was 3%. Relative risk of alcohol abuse in males was 3.64 with respect to females. Alcohol abuse was found to be significantly associated with religion (higher in Hindus with a relative risk of 8.65 in males and 5.21 in females), marital status (higher in married with a relative risk of 2.51 in males), age (higher in age group more than 20 years with a relative risk of 2.50 in males and 1.63 in females), family structure (higher in nuclear or joint families with a relative risk of 2.88 in males), educational status (higher in illiterates with a relative risk of 1.53 in males) and occupational status (higher in those engaged in agriculture with a relative risk of 1.43 in males and 1.80 in females). It was not significantly associated with per-capita income. These results have been compared with those in similar studies in the country and the possible reasons for differences, if any, have been discussed.

Alcohol abuse in a rural community in India. Part II: characteristics of alcohol users.

This part of the study dealt with the analysis of the characteristics of alcohol users. About 50% of both male and female users were between 20 and 39 years of age; 8.1% of males and only 1.3% of females used alcohol daily or several times in a week. Desi (country) liquor was the beverage used by more than 85% of the users; 77.5% of males and 96.5% of females consumed less than one quarter of a bottle of alcohol, and 65.3% of males and 93.6% of females were taking alcohol at their houses only. The reasons given for drinking by the majority of users were 'for pleasure', 'for celebration of an event' and 'status symbol'. The quantity/frequency index analysis showed that the percentage of alcoholics was 4.2 and the remaining were social drinkers. Physical, economic and social problems were reported by a significantly higher percentage of alcoholics than social drinkers. The importance of consideration of these factors in formulating a strategy of social policy in the field of alcohol use is emphasised.

Pattern of non-insulin dependent diabetes mellitus in Kuwait.

The aim of this study was to examine distinctive clinical characteristics of non-insulin dependent diabetes mellitus (NIDDM) patients in Kuwait including mode of presentation at diagnosis, family history of diabetes, therapeutic management and response to treatment. We studied 3299 Kuwaiti patients (1454 male (M) and 1845 female (F) subjects) registered in Salmiya diabetic clinic, a part of the national network of diabetes control and care programme, and located in the urban Hawally Governorate, Kuwait. The mean age of the patients was 53 years (+/- 13.9 years), and 73.8% were in the age group 45-64 years. The majority of patients (53.6%) were diagnosed as they were clinically symptomatic; in contrast a significant minority (37.8%) were diagnosed by chance mainly during investigation for unrelated events. The 8.6% of the women diagnosed during pregnancy had a high parity index 6.5 +/- 2.9. A high percentage of the diabetic patients (63%) reported a positive family history in first degree relatives. The mean duration of diabetes mellitus was 7.8 years (range 2-28 years) and 70% of the patients had diabetes mellitus for 9 years or less. The mean body mass index (BMI) was 31.8 +/- 6.3 kg/m2 and 28.5 +/- 6.3 kg/m2 in women and men, respectively. Among the diabetic women 57.7% were obese (BM > 30 kg/m2) and 30.2% were overweight (BMI 25-30 kg/m2) as compared to 33.6% and 44.3% among diabetic men, respectively. High blood pressure (> or = 160/95 mmHg) was reported in 14.9%. The main therapeutic modality in the majority of patients, (63.2%), was the administration of oral hypoglycaemic agents (OHA), while 23.7% were on a diet regimen and only 13.1% were on insulin therapy. The study throws light on the pattern of NIDDM among Kuwaiti patients. Frequent association with obesity suggests that it may be a major risk factor. The strong familial aggregation reported paves the way for future research among these families for cosegregation of a defined genetic trait with NIDDM in the Arab population subset.

Suppression of testicular and epididymal functions in a non-human primate (bonnet monkey) by combined administration of a gonadotropin-releasing hormone antagonist and testosterone buciclate.

The ability of a long-acting androgen, testosterone buciclate (TB), to induce suppression of testicular and epididymal sperm functions when given in combination with a potent GnRH antagonist (Antide) either on day 1 or 45 of Antide administration (days 1-90) as well as the ability of TB to maintain Antide-induced suppression of spermatogenesis were evaluated in adult bonnet monkeys. A group of untreated animals (group I) acted as controls. All animals given Antide and androgen simultaneously (group II) became azoospermic but at different times. When androgen administration was delayed 45 days after start of Antide treatment (group III), the mean sperm concentration remained in the normospermic range and only three animals became azoospermic. Antide given alone (group IV) induced azoospermia in three animals and oligospermia in the remaining animals; spermatogenesis recovered when Antide was withdrawn and TB was injected. In all Antide-treated animals (groups II-IV), non-motile spermatozoa or sperm with non-progressive motility and poor gel penetrability were seen in the ejaculate.

Effects of testosterone buciclate on testicular and epididymal sperm functions in bonnet monkeys (Macaca radiata)

The effects of testosterone buciclate (TB), a long-acting androgen ester given i.m. at four sites (20 mg/site) on days 1 and 91 of the study period (360 days), on reproductive and hormonal parameters were evaluated in five adult male bonnet monkeys; untreated animals (n = 5) acted as controls to monitor seasonal changes in these parameters. In control animals, testicular volume remained unchanged throughout the study; sperm count, motility and gel penetrability decreased while the percentage of spermatozoa showing retention of cytoplasmic droplet and coiled tail increased in June-July (days 210-240), preceded by reduction in serum testosterone (T) levels on days 120-150 (March-April). The TB-treated animals showed reduced testicular volume (days 90-270), suppressed sperm motility and gel penetrability (days 45-240 except on day 120), decreased sperm count (days 75-270), and an increased percentage of spermatozoa showing retention of cytoplasmic droplet and coiled tail (days 45-240 except on day 120). Even though serum T levels remained elevated until day 300, these levels were within the physiological range. The changes induced by TB were reversible. The suppression of testicular and epididymal functions by TB indicates that this long-acting androgen may have the potentiality to induce and maintain reversible sterility, but further evaluation needs to be carried out to develop an appropriate dosage regimen that would prevent return to normal functions in order to develop this long-acting androgen as a hormonal male contraceptive.(ABSTRACT TRUNCATED AT 250 WORDS)